Method for Delivering A Pharmaceutical Composition to Patient in Need Thereof

ABSTRACT

The present disclosure is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof

The present disclosure is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof

Over 15 million Americans take nonsteroidal anti-inflammatory drugs(NSAIDs) each day as a treatment for pain or inflammation.Unfortunately, many of these NSAIDs are associated with a high incidenceof gastrointestinal complications, including gastritis, dyspepsia,gastroduodenal ulcers, perforations, and bleeding. A major factorcontributing to the development of gastrointestinal lesions appears tobe the presence of acid in the stomach and upper small intestines.

During recent years, attempts have been made to reduce thegastrointestinal risk associated with taking NSAIDs by administeringagents that inhibit stomach acid secretion, such as, for example, protonpump inhibitors with the NSAID. For example, U.S. Pat. No. 6,926,907 isdirected to at least one drug dosage form comprising a proton pumpinhibitor that raises the pH of a patient's gastrointestinal tract,followed by an NSAID. This, and similar, formulations can be effectivein improving NSAID tolerability through dosages of esomeprazole andnaproxen that produce the desired pharmacodynamic response andpharmacokinetic values. Parameters that may influence the desiredpharmacodynamic response and pharmacokinetic values include, but are notlimited to, for example, the dosage of each; extent of drug absorption;extent of drug distribution, and the duration of drug administration.

There is a need for a clinically effective therapy that delivers to apatient in need thereof a pharmaceutical composition in a unit dose formcomprising naproxen, or pharmaceutically acceptable salt thereof, andesomeprazole, or pharmaceutically acceptable salt thereof, for aduration sufficient to achieve an instragastric pH of about 4 or greaterand a plasma level of naproxen that is efficacious.

In one aspect, the disclosure is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41%.

In another aspect, the disclosure is directed to a method for deliveringa pharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is about 650 hr*μg/mL.

Yet another aspect is directed to delivering a pharmaceuticalcomposition in unit dose form that provides the pharmacodynamic responseand/or pharmacokinetic values disclosed herein to a patient beingtreated for a disease or disorder selected from pain and inflammation.

A further aspect is directed to delivering a pharmaceutical compositionin unit dose form that provides the pharmacodynamic response and/orpharmacokinetic values disclosed herein to a patient being treated forosteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or acombination thereof.

A still further aspect is directed to delivering a pharmaceuticalcomposition in unit dose form that provides the pharmacodynamic responseand/or pharmacokinetic values disclosed herein to an at risk patient.

Another aspect is directed to delivering a pharmaceutical composition inunit dose form that provides the pharmacodynamic response and/orpharmacokinetic values disclosed herein to an at risk patient beingtreated for a disease or disorder selected from pain and inflammation.

A further aspect is directed to delivering a pharmaceutical compositionin unit dose form that provides the pharmacodynamic response and/orpharmacokinetic values disclosed herein to an at risk patient beingtreated for osteoarthritis, rheumatoid arthritis, ankylosingspondylitis, or a combination thereof.

Yet another aspect is directed to delivering a pharmaceuticalcomposition in unit dosage form that provides the pharmacodynamicresponse and/or pharmacokinetic values disclosed herein via a multilayertablet comprising at least one core and at least a first layer and asecond layer, wherein:

-   -   i) said core comprises naproxen, or pharmaceutically acceptable        salt thereof;    -   ii) said first layer is a coating that at least begins to        release the naproxen, or pharmaceutically acceptable salt        thereof, when the pH of the surrounding medium is at about 3.5        or greater; and    -   iii) said second layer is esomeprazole, or pharmaceutically        acceptable salt thereof, wherein said esomeprazole, or        pharmaceutically acceptable salt thereof, is released at a pH of        from about 0 or greater.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Mean pH data over 24 hours on day 9 per protocol population.Treatment A=PN400/E30; B=PN400/E20; C=PN400/E10; D=EC E20+naproxen.

FIG. 2: Mean intragastric pH data over 24 hours on day 1 per protocolpopulation. Treatment A=PN400/E30; B=PN400/E20; C=PN400/E10; D=ECE20+naproxen.

FIG. 3: Mean plasma esomeprazole concentration vs. time curves on day 1.

FIG. 4: Mean plasma esomeprazole concentration vs. time curves on day 9.

FIG. 5: Mean plasma naproxen concentration vs. time curves on day 1.

FIG. 6: Mean plasma naproxen concentration vs. time curves on day 9.

FIG. 7: Correlation of plasma exposure to esomeprazole with effect onintragastric pH on day 9.

FIG. 8A: Mean pH data and mean naproxen concentration vs. time profilesover a 24-hour period on day 9: Treatment B (PN 400/E20).

FIG. 8B: Mean pH data and mean naproxen concentration vs. time profilesover a 24-hour period on day 9: Treatment D (EC E20+naproxen).

FIG. 9: Mean Plasma Naproxen Concentration vs. Time Curves by Treatment(All Subjects)

FIG. 10: Mean Plasma Esomeprazole Concentration vs. Time Curves byTreatment.

FIG. 11: Mean plasma concentrations of naproxen and esomeprazolefollowing single dose administration of PN 400/E20 over a 24-hourperiod. FIG. 11 combines the esomeprazole and naproxen concentration vs.time curves derived for PN 400, as depicted in FIG. 9 (for naproxen) andFIG. 10 (for esomeprazole), at 30 minute timepoints through 4 hours, 2hour timepoints from 4 to 12 hours, and 4 hour timepoints from 12 to 24hours. Because FIGS. 9 and 10 present more frequent timepoints, theappearance of the curves in FIG. 11 may differ slightly from theirappearance in FIGS. 9 and 10.

Abbreviations and/or special terms that may be used herein are set forthin Table 1 and the text that follows.

TABLE 1 Abbreviations and Special Terms Abbreviation Explanation ANOVAanalysis of variance AUC area under the plasma concentration-time curveAUC_(0-10,am) AUC from time zero (time of AM dosing) to 10 hours afterthe AM dose AUC_(0-14,pm) AUC from time zero (time of PM dosing) to 14hours after the PM dose AUC₀₋₂₄ AUC from time zero (time of AM dosing)to 24 hours after the AM dose AUC_(0-t,am) AUC from time zero to thelast time point with measurable drug concentration following AM dosingAUC_(0-t,pm) AUC from time zero to the last time point with measurabledrug concentration following PM dosing AUC_(0-t) AUC from time zero tothe last time point with measurable drug concentration Bid twice dailyBQL below the lower limit of quantification CBC complete blood count CIconfidence interval C_(max,am) maximum plasma concentration after the AMdose C_(max,pm) maximum plasma concentration after the PM dose CVcoefficient of variation GCP Good Clinical Practice EC enteric-coatedECG electrocardiogram eCRF electronic case report form E_(max) maximalresponse or pharmacodynamic effect GI Gastrointestinal GLSM Geometricleast-squares mean HPLC/MS/MS high pressure liquid chromatography tandemmass spectrometry ITT intent-to-treat LLOQ lower limit of quantificationLS least square MedDRA Medical Dictionary for Regulatoy Activities MRMmultiple reaction monitoring λ_(z,am) apparent first-order eliminationrate constant following AM dosing λ_(z,pm) apparent first-orderelimination rate constant following PM dosing Ln natural log PDpharmacodynamic(s) PDS Phoenix Data Systems PK pharmacokinetic(s) PP perprotocol PPD Pharmaceutical Product Development PPI proton pumpinhibitor QC quality control SD standard deviation SE standard error SOCsystem organ class SPE solid phase extraction t_(lag,am) time to thefirst measurable plasma concentration following the AM dose (t_(lag,am))t_(lag,pm) time to the first measurable plasma concentration followingthe PM dose (t_(lag,am)) t_(last) last time point with measurable drugconcentration t_(max) time to maximum plasma concentration t_(1/2,am)apparent plasma half-life following the AM dose t_(1/2,pm) apparentplasma half-life following the PM dose

The term “at risk patient” refers to patient(s) at risk for NSAIDassociated ulcer due to age or a documented history of gastric ulcers,or receiving concomitant LDA (low dose aspirin). In one embodiment, theat risk patient is a patient at risk for NSAID associated ulcer due toage greater than or equal to 50 years. In another embodiment, the atrisk patient is a patient at risk for NSAID associated ulcer due toconcomitant aspirin use. In yet another embodiment, the at risk patientis a patient at risk for NSAID associated ulcer due to history of uppergastrointestinal (UGI) ulcer or bleeding

The term “pharmaceutically-acceptable”, as employed herein, indicatesthe subject matter being identified as “pharmaceutically acceptable” issuitable and physiologically acceptable for administration to apatient/subject. For example, the term “pharmaceutically acceptablesalt(s)” denotes suitable and physiologically acceptable salt(s).

The phrase “naproxen, or pharmaceutically acceptable salt thereof”refers to the free base of naproxen, pharmaceutically acceptable salt(s)of naproxen, and/or mixtures of the free base of naproxen and at leastone pharmaceutically acceptable salt of naproxen.

The phrase “esomeprazole, or pharmaceutically acceptable salt thereof”refers to the free base of esomeprazole, pharmaceutically acceptablesalt(s) of esomeprazole, and/or mixtures of the free base ofesomeprazole and at least one pharmaceutically acceptable salt ofesomeprazole.

The term “unit dosage form” (or “unit dose form”) as used herein refersto a single entity for drug administration. For example, a single tabletor capsule containing both esomeprazole and naproxen is a unit dosageform. Unit dosage forms of the present disclosure provide for sequentialdrug release in a way that elevates gastric pH and reduces thedeleterious effects of naproxen on the gastroduodenal mucosa, i.e., theesomeprazole is released first and the release of naproxen is delayeduntil after the pH in the GI tract has risen to 3.5 or greater. A “unitdosage form” (or “unit dose form”) may also be referred to as a “fixeddosage form” (or “fixed dose form”) or fixed dosage combination (orfixed dose combination“) and are otherwise interchangeable.

For the values provided herein, the term “about” indicates a givennumber may vary by at least 5%, with variations of 10%, 15% or 20% beingpossible.

With regard to the pharmacokinetic and/or pharmacodynamic valuesprovided herein, the degree of variation is reflected in SDs and % CVvalues. The % CV=SD/mean×100; the SD=(% CV×mean) divided by 100. It canbe expected that approximately 68% of patients will be within one SD ofthe mean and approximately 95% of patients will be within two SDs of themean. The pharmacokinetic and pharmacodynamic values presented hereinare average values, rounded to the nearest whole number, and are basedupon results obtained from multiple individuals. As a result, the valuespresented herein may vary from one patient to another. This variation isreflected in the term “about.”

With regard to the dosages of each of naproxen, or pharmaceuticallyacceptable salt thereof and/or esomeprazole, or pharmaceuticallyacceptable salt thereof the term “about” is intended to reflectvariations from the specifically identified dosages that are acceptablewithin the art.

With regard to time periods referred to herein, the term “about” isintended to reflect variations from the specifically identified timeperiods that are acceptable within the art.

With regard to the numerical % coefficient of variation values and/orranges used herein, the term “about” is intended to reflect variationsabove and below the stated numerical value and/or range that that mayachieve substantially the same results as the stated number.

With regard to the pH values and/or ranges recited herein, the term“about” is intended to to capture variations above and below the statednumber that may achieve substantially the same results as the statednumber.

With regard to the term numerical values used in conjunction with thephrase “substantially free”, the term is intended to to capturevariations above and below the stated number that may achievesubstantially the same results as the stated number.

The phrase “substantially free” means from about 95% to about 99.99%free. In one embodiment, substantially free means about 95% free. Inanother embodiment, the term substantially free means about 96% free. Instill another embodiment, the term substantially free means about 97%free. In yet another embodiment, the term substantially free means about98% free. In a further embodiment, the term substantially free meansabout 99% free. In still a further embodiment, the term substantiallyfree means about 99.99% free.

In the present disclosure, each of the variously stated ranges isintended to be continuous so as to include each numerical parameterbetween the stated minimum and maximum value of each range. For Example,a range of about 1 to about 4 includes about 1, 1, about 2, 2, about 3,3, about 4, and 4.

One embodiment is directed to a method for delivering a pharmaceuticalcomposition to a patient in need thereof, comprising: administering tosaid patient a pharmaceutical composition in unit dose form comprisingnaproxen, or pharmaceutically acceptable salt thereof, and esomeprazole,or pharmaceutically acceptable salt thereof, wherein said esomeprazole,or pharmaceutically acceptable salt thereof, is released from said unitdose form at a pH of from about 0 or greater to target: a mean % time atwhich intragastric pH remains at about 4.0 or greater for about a 24hour period after reaching steady state of at least about 41%.

Steady state levels of naproxen or esomeprazole are generally reached inabout 4 to 5 days, about 5 to 6 days, about 6 to 7 days, about 7 to 8days, about 8 to 9 days, or about 9 to 10 days after [twice daily]delivery of the pharmaceutical compositions in unit dose form disclosedherein. In other embodiments, steady state levels of naproxen oresomeprazole are reached in about 4 days, about 5 days, about 6 days,about 7 days, about 8 days, about 9 days, or about 10 days.

In other embodiments, the mean % time at which intragastric pH remainsat about 4.0 or greater for a 24 hour period after reaching steady stateis at least about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 71%, about 75%, about 77%, about 80%, about 85%,about 90%, or about 95%.

Another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41% and a pharmacokinetic (pk) profile having a mean maximumplasma concentration (C_(max)) for naproxen of at least 76 μg/mL with acoefficient of variation ranging from 17-23.

A further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41% and a pharmacokinetic (pk) profile having a mean maximumplasma concentration (C_(max)) for naproxen of about 76 μg/mL.

Yet another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41% and a pharmacokinetic (pk) profile having a mean areaunder the plasma concentration-time curve from time zero when first doseis administered to about 24 hours after the first dose is administered(AUC₀₋₂₄) for esomeprazole of at least 1500 hr*μg/mL with a %coefficient of variation ranging from 40-80.

Yet a further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41% and a pharmacokinetic (pk) profile having a mean areaunder the plasma concentration-time curve from time zero when first doseis administered to about 24 hours after the first dose is administered(AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

Still yet another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41%; and a pharmacokinetic (pk) profile having a meanmaximum plasma concentration (C_(max)) for naproxen of at least 76 μg/mLwith a coefficient of variation ranging from 17-23 and a mean area underthe plasma concentration-time curve from time zero when first dose isadministered to about 24 hours after the first dose is administered(AUC₀₋₂₄) for esomeprazole of at least 1500 hr*μg/mL with a %coefficient of variation ranging from 40-80.

Still even yet another embodiment is directed to a method for deliveringa pharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state of atleast about 41%; and a pharmacokinetic (pk) profile having a meanmaximum plasma concentration (C_(max)) for naproxen of about 76 μg/mLand a mean area under the plasma concentration-time curve from time zerowhen first dose is administered to about 24 hours after the first doseis administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

A still even further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a pharmacokinetic (pk) profile having a mean maximum plasmaconcentration (C_(max)) for naproxen of at least 76 μg/mL with a %coefficient of variation ranging from 17-23.

Yet a further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: a pharmacokinetic (pk) profile having a mean maximum plasmaconcentration (C_(max)) for naproxen of about 76 μg/mL.

A yet still further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: and a pharmacokinetic (pk) profile having mean area under theplasma concentration-time curve from time zero when first dose isadministered to about 24 hours after the first dose is administered(AUC₀₋₂₄) for esomeprazole of at least 1500 hr*μg/mL with a %coefficient of variation ranging from 40-80.

A yet even further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater totarget: and a pharmacokinetic (pk) profile having mean area under theplasma concentration-time curve from time zero when first dose isadministered to about 24 hours after the first dose is administered(AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

A further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μg/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85.

A yet further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from 0 or greater, whereinone unit dose form is administered as an AM dose and a second doseadministered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL.

A still further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μm/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours.

A yet still further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours.

A yet even still further embodiment is directed to a method fordelivering a pharmaceutical composition to a patient in need thereof,comprising: administering to said patient a pharmaceutical compositionin unit dose form comprising naproxen, or pharmaceutically acceptablesalt thereof, and esomeprazole, or pharmaceutically acceptable saltthereof, wherein said esomeprazole, or pharmaceutically acceptable saltthereof, is released from said unit dose form at a pH of from about 0 orgreater, wherein one unit dose form is administered as an AM dose and asecond dose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85.

A further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL.

A yet still even further embodiment is directed to a method fordelivering a pharmaceutical composition to a patient in need thereof,comprising: administering to said patient a pharmaceutical compositionin unit dose form comprising naproxen, or pharmaceutically acceptablesalt thereof, and esomeprazole, or pharmaceutically acceptable saltthereof, wherein said esomeprazole, or pharmaceutically acceptable saltthereof, is released from said unit dose form at a pH of from about 0 orgreater, wherein one unit dose form is administered as an AM dose and asecond dose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μg/mL            with % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85; and    -   iii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%.

A still even further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about least 81 μg/mL            and a median time to maximum concentration (T_(max)) of from            about 2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL; and    -   iii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%.

Still yet another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μg/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%.

A still yet further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%.

Even still yet a further embodiment is directed to a method fordelivering a pharmaceutical composition to a patient in need thereof,comprising: administering to said patient a pharmaceutical compositionin unit dose form comprising naproxen, or pharmaceutically acceptablesalt thereof, and esomeprazole, or pharmaceutically acceptable saltthereof, wherein said esomeprazole is released from said unit dose format a pH of from 0 or greater, wherein one unit dose form is administeredas an AM dose and a second dose administered about 10 hours later as aPM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85; and    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour after reaching steady state        period of at least about 41%.

An even still further embodiment is directed to a method for deliveringa pharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole is released from said unit dose form at a pH of from 0or greater, wherein one unit dose form is administered as an AM dose anda second dose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL; and    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%.

A yet still even further embodiment is directed to a method fordelivering a pharmaceutical composition to a patient in need thereof,comprising: administering to said patient a pharmaceutical compositionin unit dose form comprising naproxen, or pharmaceutically acceptablesalt thereof, and esomeprazole, or pharmaceutically acceptable saltthereof, wherein said esomeprazole, or pharmaceutically acceptable saltthereof, is released from said unit dose form at a pH of from about 0 orgreater, wherein one unit dose form is administered as an AM dose and asecond dose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μg/mL            with a % coefficient of variation of ranging from 18-23 and            a median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to 10 hours after the AM dose is administered            (AUC_(0-10,am)) is at least 850 hr*μg/mL with a %            coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85;    -   iii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%; and    -   iv) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

Another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about least 81 μg/mL            and a median time to maximum concentration (T_(max)) of from            about 2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL;    -   iii) a mean % time at which intragastric pH remains at about 4.0        or greater for a 24 hour period after reaching steady state of        at least about 41%; and    -   iv) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

A further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μg/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μg/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

A yet further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

A still further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85; and    -   ii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole is at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

Still a further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μg/mL; and    -   ii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

Yet another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μm/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μm/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole is at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

Yet still another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours; and    -   ii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μg/mL.

Yet a further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) is at least 850 hr*μg/mL with a            % coefficient of variation ranging from 45-70, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) is at least 650 hr*μg/mL with a            % coefficient of variation ranging from 50-85;    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole is at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

Yet a still further embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for esomeprazole where:        -   a) the AM dose has a mean area under the plasma            concentration-time curve from time zero when the AM dose is            administered to about 10 hours after the AM dose is            administered (AUC_(0-10,am)) of about 850 hr*μg/mL, and        -   b) the PM dose has a mean area under the plasma            concentration-time curve from time zero when the PM dose is            administered to about 14 hours after the PM dose is            administered (AUC_(0-14,pm)) of about 650 hr*μm/mL;    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole of about 1500 hr*μm/mL.

Yet another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of at least 81 μm/mL with            a % coefficient of variation ranging from 22-23 and a median            time to maximum concentration (T_(max)) of from about 2.5 to            about 4 hours, and        -   b) the PM dose has a mean C_(max) of at least 76.2 μm/mL            with a % coefficient of variation ranging from 18-23 and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole is at least 1500        hr*μg/mL with a % coefficient of variation ranging from 40-80.

Yet still another embodiment is directed to a method for delivering apharmaceutical composition to a patient in need thereof, comprising:administering to said patient a pharmaceutical composition in unit doseform comprising naproxen, or pharmaceutically acceptable salt thereof,and esomeprazole, or pharmaceutically acceptable salt thereof, whereinsaid esomeprazole, or pharmaceutically acceptable salt thereof, isreleased from said unit dose form at a pH of from about 0 or greater,wherein one unit dose form is administered as an AM dose and a seconddose administered about 10 hours later as a PM dose to target:

-   -   i) a pk profile for naproxen where:        -   a) the AM dose has a mean C_(max) of about 81 μg/mL and a            median time to maximum concentration (T_(max)) of from about            2.5 to about 4 hours, and        -   b) the PM dose has a mean C_(max) of about 76.2 μg/mL and a            median T_(max) of from about 10 to about 14 hours;    -   ii) a mean % time at which intragastric pH remains at about 4.0        or greater for about a 24 hour period after reaching steady        state of at least about 41%; and    -   iii) a pharmacokinetic (pk) profile having a mean area under the        plasma concentration-time curve from time zero when first dose        is administered to about 24 hours after the first dose is        administered (AUC₀₋₂₄) for esomeprazole is about 1500 hr*μg/mL.

In another embodiment, naproxen can be present as the free base in anamount of from about 500 mg.

In still another embodiment, naproxen can be present as the free base inan amount of about 500 mg.

In yet another embodiment, naproxen can be present in equivalent amountsof pharmaceutically acceptable salts of naproxen, e.g., sodium naproxen.

In a further embodiment, esomeprazole can be present as a magnesiumsalt.

In an even further embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, can be present in an amount to provide fromabout 10 mg to about 30 mg of esomeprazole.

In a further embodiment, esomeprazole, or pharmaceutically acceptablesalt thereof, can be present in an amount to provide about 15 mg ofesomeprazole.

In yet an even further embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, can be present in an amount to provide about 20mg of esomeprazole.

In still yet another embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, can be present in an amount to provide about 30mg of esomeprazole.

In still another embodiment, the mean % time at which intragastric pHremains at about 4.0 or greater for about a 24 hour period afterreaching steady state is at least about 60%.

In yet another embodiment, the mean % time at which intragastric pHremains at about 4.0 or greater for about a 24 hour period afterreaching steady state is at least about 71%.

In still yet an even further embodiment, the mean % time at whichintragastric pH remains at about 4.0 or greater for about a 24 hourperiod after reaching steady state is at least about 77%.

In an even still further embodiment, the mean maximum plasmaconcentration (C_(max)) for naproxen is at least 79 μg/mL with a %coefficient of variation ranging from 17-23.

In a further embodiment, the mean maximum plasma concentration (C_(max))for naproxen is about 79 μg/mL.

In yet an even still further embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is 2134 hr*μg/mL with a coefficient of variation of 74.

In another embodiment, the mean area under the plasma concentration-timecurve from time zero when first dose is administered to about 24 hoursafter the first dose is administered (AUC₀₋₂₄) for esomeprazole is about2134 hr*μg/mL.

In yet another embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is about 2000 hr*μg/mL with a % coefficient of variationranging from 40-80.

n yet another embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is about 2000 hr*μg/mL.

In still another embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is about 1500 hr*μg/mL.

In a still further embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is 4911 hr*μg/mL with a % coefficient of variation of 42.

In yet still a further embodiment, the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is about 4911 hr*μg/mL.

In one embodiment, the pharmaceutical composition in unit dose formcomprises about 500 mg of said naproxen, or pharmaceutically acceptablesalt thereof, and about 20mg of said esomeprazole, or pharmaceuticallyacceptable salt thereof

In another embodiment, the pharmaceutical composition in unit dose formcomprises about 500 mg of said naproxen, or pharmaceutically acceptablesalt thereof, and about 30mg of said esomeprazole, or pharmaceuticallyacceptable salt thereof.

In yet another embodiment, the unit dose form is administered twice aday for at least 6 days.

In still another embodiment, the unit dose form is administered twice aday for at least 9 days.

In still yet another embodiment, the patient in need thereof is an atrisk patient.

In yet another embodiment, the at risk patient is being treated for adisease or disorder selected from pain and inflammation.

In a further embodiment, the at risk patient is being treated forosteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or acombination thereof.

In another embodiment, the patient in need thereof is being treated fora disease or disorder selected from pain and inflammation.

In yet another embodiment, the patient in need thereof is being treatedfor osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or acombination thereof.

In yet another embodiment, the mean C_(max) for said AM dose of naproxenis 86.2 μg/mL with a % coefficient of variation of 22 and said medianT_(max) is about 3.0 hours; and the mean C_(max) for said PM dose is76.8 μg/mL with a % coefficient of variation of 18 and said medianT_(max) is about 10 hours.

In another embodiment, the mean C_(max) for said AM dose of naproxen isabout 86.2 μg/mL and said median T_(max) is about 3.0 hours; and themean C_(max) for said PM dose is about 76.8 μg/mL and said medianT_(max) is about 10 hours.

In still another embodiment, the mean C_(max) for said AM dose ofnaproxen is 80.9 μg/mL with a % coefficient of variation of 23 and saidmedian T_(max) is about 3.0 hours; and b) the mean C_(max) for said PMdose is 76.2 μg/mL with a % coefficient of variation of 23 and saidmedian T_(max) is about 10.4 hours.

In still yet another embodiment, the mean C_(max) for said AM dose ofnaproxen is about 80.9 μg/mL and said median T_(max) is about 3.0 hours;and b) the mean C_(max) for said PM dose is about 76.2 μg/mL and saidmedian T_(max) is about 10.4 hours.

In yet still another embodiment, the mean area under the plasmaconcentration-time curve from time zero when the AM dose is administeredto about 10 hours after the AM dose is administered (AUC_(0-10,am)) forsaid AM dose of esomeprazole is 1216 hr*μg/mL with a % coefficient ofvariation of 69, and the mean area under the plasma concentration-timecurve from time zero when the PM dose is administered to about 14 hoursafter the PM dose is administered (AUC_(0-14,pm)) for said PM dose ofesomeprazole is 919 hr*μg/mL with a % coefficient of variation of 84.

In a further embodiment, the PM dose has a mean area under the plasmaconcentration-time curve from time zero when the PM dose is administeredto about 14 hours after the PM dose is administered (AUC_(0-14,p)) is atleast 900 hr*μg/mL with a % coefficient of variation ranging from 50-85.

In a still further embodiment, the PM dose has a mean area under theplasma concentration-time curve from time zero when the PM dose isadministered to about 14 hours after the PM dose is administered(AUC_(0-14,pm)) of about 900 hr*μg/mL.

In a still even further embodiment, the PM dose has a mean area underthe plasma concentration-time curve from time zero when the PM dose isadministered to about 14 hours after the PM dose is administered(AUC_(0-14,pm)) of about 2100 hr*μg/mL.

In yet another embodiment, the mean area under the plasmaconcentration-time curve from time zero when the AM dose is administeredto about 10 hours after the AM dose is administered (AUC_(0-10,am)) forsaid AM dose of esomeprazole is about 1216 hr*μg/mL, and the mean areaunder the plasma concentration-time curve from time zero when the PMdose is administered to about 14 hours after the PM dose is administered(AUC_(0-14,pm)) for said PM dose of esomeprazole is about 919 hr*μg/mL.

In an even further embodiment, the AM dose has a mean area under theplasma concentration-time curve from time zero when the AM dose isadministered to about 10 hours after the AM dose is administered(AUC_(0-10,am)) is at least 1200 hr*μg/mL with a % coefficient ofvariation ranging from 45-70.

In a still even further embodiment, the AM dose has a mean area underthe plasma concentration-time curve from time zero when the AM dose isadministered to about 10 hours after the AM dose is administered(AUC_(0-10,am)) of about 1200 hr*μg/mL .

In a till even further embodiment, the AM dose has a mean area under theplasma concentration-time curve from time zero when the AM dose isadministered to about 10 hours after the AM dose is administered(AUC_(0-10,am)) of about 2800 hr*μg/mL.

In still yet a further embodiment, the mean area under the plasmaconcentration-time curve from time zero when the AM dose is administeredto about 10 hours after the AM dose is administered (AUC_(0-10,am)) forsaid AM dose of esomeprazole is 2779 hr*μg/mL with a % coefficient ofvariation of 45, and the mean area under the plasma concentration-timecurve from time zero when the PM dose is administered to about 14 hoursafter the PM dose is administered (AUC_(0-14,pm)) for said PM dose ofesomeprazole is 2066 hr*μg/mL with a % coefficient of variation of 53.

In an even further embodiment, the mean area under the plasmaconcentration-time curve from time zero when the AM dose is administeredto about 10 hours after the AM dose is administered (AUC_(0-10,am)) forsaid AM dose of esomeprazole is about 2779 hr*μg/mL, and the mean areaunder the plasma concentration-time curve from time zero when the PMdose is administered to about 14 hours after the PM dose is administered(AUC_(0-14,pm)) for said PM dose of esomeprazole is about 2066 hr*μg/mL.

In an even further embodiment, the pharmaceutical composition in unitdose form is a multilayer tablet comprising at least one core and atleast a first layer and a second layer, wherein said core comprisesnaproxen, or pharmaceutically acceptable salt thereof; said first layeris a coating that at least begins to release the naproxen, orpharmaceutically acceptable salt thereof, when the pH of the surroundingmedium of about 3.5 or greater; said second layer is esomeprazole, orpharmaceutically acceptable salt thereof, wherein said esomeprazole, orpharmaceutically acceptable salt thereof, is released at a pH of fromabout 0 or greater.

In an even further embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, is released at a pH of from 0 or greater.

In another embodiment, esomeprazole, or pharmaceutically acceptable saltthereof, is released at a pH of from about 1 or greater.

In a further embodiment, esomeprazole, or pharmaceutically acceptablesalt thereof, is released at a pH of from 1 or greater.

In still another embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, is released at a pH of from about 0 to about 2.

In yet a further embodiment, esomeprazole, or pharmaceuticallyacceptable salt thereof, is released at a pH of from 0 to 2.

In yet still another embodiment, at least a portion of saidesomeprazole, or pharmaceutically acceptable salt thereof, is not coatedwith an enteric coating.

In even yet still another embodiment, the first layer is an entericcoating.

In an even further embodiment, the pharmaceutical composition in unitdose form is a multilayer tablet comprising a core comprising naproxen,or pharmaceutically acceptable salt thereof, and a first layercomprising a coating that at least begins releasing the naproxen whenthe pH of the surrounding medium is about 3.5 or greater and a secondlayer comprising esomeprazole, or pharmaceutically acceptable saltthereof, wherein at least a portion of said esomeprazole, orpharmaceutically acceptable salt thereof, is not surrounded by anenteric coating.

In another embodiment, the first layer is a coating that at least beginsto release the naproxen when the pH of the surrounding medium is about4.0, 4.5, 5.0 or greater.

In still yet another embodiment, said first layer begins to release thenaproxen when the pH of the surrounding medium is at about 4.0 orgreater.

In a further embodiment, said first layer begins to release the naproxenwhen the pH of the surrounding medium is at about 4.5 or greater.

In yet a further embodiment, said first layer begins to release thenaproxen when the pH of the surrounding medium is at about 5.0 orgreater.

In one embodiment, at least about 95% of the esomeprazole, orpharmaceutically acceptable salt thereof, is not surrounded by anenteric coating.

In another embodiment, at least about 99% of the esomeprazole, orpharmaceutically acceptable salt thereof, is not surrounded by anenteric coating. In yet another embodiment, at least about 99.5% of theesomeprazole, or pharmaceutically acceptable salt thereof, is notsurrounded by an enteric coating.

In yet another embodiment, the multilayer tablet is substantially freeof sodium bicarbonate.

In still another embodiment, the multilayer tablet is completely (i.e.,100%) free of sodium bicarbonate.

In one embodiment, the dosing regimen is twice a day.

In another embodiment, the doses can be separated by a period of atleast about 10 hours.

In another embodiment, the pharmaceutical composition in unit dose formis given about 1 hour before a patient ingests a meal.

In another embodiment, the pharmaceutical compositions of the presentdisclosure may be administered therapeutically to patients either shortterm or over a longer period of time, for example chronically.

In other embodiments, long term or chronic administration of thepharmaceutical compositions disclosed herein can result in intragastricpH being at least about 4.0 or greater a higher percentage of time per24 hour period versus short-term administration. For example,administration of certain pharmaceutical compositions may result in ahigher percentage time of intragastric pH being greater than about 4.0on Day 9 versus Day 1 of treatment.

In another embodiment, the method for delivering a pharmaceuticalcomposition to a patient in need thereof, comprises administering to thepatient a pharmaceutical composition in unit dose form comprisingnaproxen, or pharmaceutically acceptable salt thereof, and esomeprazole,or pharmaceutically acceptable salt thereof, wherein intragastric pH isincreased to at least about 4.0 within one hour of administration.

In another embodiment, intragastric pH is increased to at least about4.0 or greater within 30 or 45 minutes of administration

The pharmaceutical compositions disclosed herein include, but are notlimited to, for example, tablets and capsules that can be made inaccordance with methods that are standard in the art (see, e.g.,Remington's Pharmaceutical Sciences, 16^(th) ed., A Oslo editor, Easton,Pa. (1980)).

Suitable carriers include, but are not limited to: water; saltsolutions; alcohols; gum arabic; vegetable oils; benzyl alcohols;polyethylene glycols; gelatin; carbohydrates such as lactose, amylose orstarch; magnesium stearate; talc; silicic acid; paraffin; perfume oil;fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc.

The pharmaceutical compositions disclosed herein can be sterilized and,if desired, mixed with, for example, auxiliary agents, such as, forexample, preservatives; stabilizers; buffers; coloring agents; andflavoring agents.

In one embodiment, at least one of the layers comprising thepharmaceutical compositions disclosed herein may be applied usingstandard coating techniques. The layer materials may be dissolved ordispersed in organic or aqueous solvents. The layer materials mayinclude, but are not limited to, for example, one or more of thefollowing materials: methacrylic acid copolymers, shellac,hydroxypropylmethcellulose phthalate, polyvinyl acetate phthalate,hydroxypropylmethyl-cellulose trimellitate,carboxymethylethyl-cellulose, cellulose acetate phthalate, and/or othersuitable polymer(s). The pH at which the first layer dissolves can becontrolled by the polymer or combination of polymers selected and/orratio of pendant groups. For example, dissolution characteristics of thepolymer film can be altered by the ratio of free carboxyl groups toester groups. The layers may also contain pharmaceutically acceptableplasticizers, such as, for example, triethyl citrate, dibutyl phthalate,triacetin, polyethylene glycols, polysorbates or other plasticizers.Additives, such as, for example, dispersants, colorants, anti-adhering,and anti-foaming agents may also be used.

In one embodiment, the pharmaceutical compositions disclosed herein canbe in the form of a bi- or multi-layer tablet. In a bi-layer tablet, oneportion/layer of the tablet contains the esomeprazole, orpharmaceutically acceptable salt thereof, in the required dose alongwith appropriate excipients, agents to aid dissolution, lubricants,fillers, etc.; and a second portion/layer of the tablet contains theNSAID in the required dose along with other excipients, dissolutionagents, lubricants, fillers, etc.

In another embodiment, the naproxen portion/layer is surrounded by apolymeric coating that dissolves at a pH of at least about 3.5 orgreater.

In yet another embodiment, the naproxen portion/layer is surrounded by apolymeric coating that dissolves at a pH of at least about 4 or greater.

The naproxen, or pharmaceutically acceptable salt thereof, may begranulated by methods such as slugging, low- or high-shear granulation,wet granulation, or fluidized-bed granulation. Of these processes,slugging generally produces tablets of less hardness and greaterfriability. Low-shear granulation, high-shear granulation, wetgranulation and fluidized-bed granulation generally produce harder, lessfriable tablets.

EXAMPLES(S)

The invention is further defined in the following Example(s). It shouldbe understood the Example(s) are given by way of illustration only. Fromthe above discussion and the Example(s), one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative example(s)set forth hereinbelow, but rather defined by the claims appended hereto.

Example 1

A randomized, open-label, 4-way cross-over study to evaluate the effecton days 1 and 9 of twice daily oral administration of three PN 400formulations (enteric coated naproxen 500 mg combined with non-entericcoated esomeprazole 10, 20, or 30 mg) versus the effect of twice dailyoral administration of a separate 500 mg non-enteric coated naproxentablet and once daily oral administration of a separate EC esomeprazole(20 mg) capsule (Nexium® 20mg capsule) on the 24-hour intragastric pHand pharmacokinetic parameters (i.e., C_(max), T_(max), AUC_(0-10,am),AUC_(0-14,pm), AUC₀₋₂₄, AUC_(0-1,am), and AUC_(0-1,pm)) of healthyvolunteers. The PN400 tablet is a multilayer tablet comprising an innercore of naproxen surrounded by a first layer comprising an entericcoating and a second layer comprising non-enteric coated esomeprazole.

The study was designed to compare the pharmacodynamic (PD) measurementsof intragastric pH (percent time of pH>4.0) on Day 9 of three PN 400formulations following twice daily (BID) administration versus acombination of non-enteric coated naproxen taken BID and EC esomeprazole(20 mg) taken once daily.

The study was also designed to compare the PD measurement ofintragastric pH (percent time of pH>4.0) on Day 1 of three PN 400formulations following BID administration versus a combination ofnon-enteric coated naproxen taken BID and EC esomeprazole taken oncedaily; and assess the pharmacokinetics of esomeprazole and naproxen onDay 1 and Day 9 in each of the treatment groups.

This was a single-center study in 28 healthy adults. The study consistedof four 9-day treatment periods. The first, second and third treatmentperiods were followed by a washout period of at least 12 days. Eligiblesubjects reported to the Phase 1 unit in the PM of Day 0 for screening.

Screening procedures included procurement of informed consent, medicaland drug history, physical examination, vital signs, 12-leadelectrocardiogram (ECG), clinical laboratory testing, urine drug screen,pregnancy test for females of childbearing potential, and helicobacterpylori breath test. Clinical laboratory tests, physical examination, andmeasurement of vital signs were performed at Screening and the FinalVisit. A 12-lead electrocardiogram (ECG) and 13C-urea breath test toscreen for possible helicobacter pylori infection were performed atScreening. A urine drug screen for all subjects and a urine pregnancytest for women of childbearing potential were performed on Days 0 and 8of each treatment period. On Days 1 and 9 of each treatment period,24-hour blood sampling was performed for pharmacokinetic (PK)assessments. Subjects were instructed to report to the Phase 1 unitwithin 14 days of the initiation of screening procedures.

28 subjects were planned, randomized and treated, and data for 25subjects were analyzed as the Per-Protocol (PP) population; theIntent-to-Treat (ITT), Safety and PK populations included all 28subjects. Subjects were healthy males or non-lactating, non-pregnantfemales 18 to 55 years of age with a body mass index of 19-32 kg/m²,were helicobacter pylori (H. pylori) negative, and were generally ingood health with no history of peptic ulcer disease or otheracid-related gastrointestinal (GI) symptoms.

Subject enrollment and disposition are summarized in Table 2.Twenty-eight subjects were randomized and treated at one investigationalcenter; these subjects comprised the PK population. One subject droppedout of the study for personal reasons after completing 3 treatmentperiods (Treatments A [PN 400/E30], B [PN 400/E20] and D [ECE20+naproxen]). The PP population included 25 subjects.

TABLE 2 Subject Enrollment and Disposition - All Subjects Subjects (%) N= 28 Subjects Randomized and Treated 28 (100) Safety Population 28 (100)Intent-to-Treat Population 28 (100) Per Protocol Population 25 (89)  PKPopulation 28 (100) Subjects Completed 27 (96)  Subjects WithdrawnPrematurely 1 (4)  Adverse event 0 Withdrew consent 0 Lost to follow-up0 Other 1 (4) 

The demographic characteristics of the ITT population at Screening aresummarized in Table 3. The study population was 68% male and had a meanage of approximately 25 years. All subjects were white and non-Hispanic.

TABLE 3 Demographic Characteristics - ITT Population Total Subjects N =28 Age (years) n 28 Mean (SD) 24.9 (3.9) Median 24 Range 18-34 Gender -n (%) Males  19 (68) Females  9 (32) Race - n (%) White  28 (100)Black/African American 0 Asian 0 Other 0 Ethnicity - n (%) Hispanic orLatino 0 Not Hispanic or Latino  28 (100) Height (in) n 28 Mean (SD)70.1 (4.1) Median 70.0 Range 63-79 Weight (lb) n 28 Mean (SD) 177.9(34.6) Median 178.0 Range 112-250

At any time during Screening but at least prior to Day 1 of the firsttreatment period, subjects had their lower esophageal sphincter (LES)located to determine accurate placement of the pH probe.

Subjects were randomized on Day 1 of the first treatment period into 1of 4 dosing sequences to receive a 9-day course of each one of thefollowing daily treatment regimens in a crossover fashion:

-   -   Treatment A: 1 tablet PN 400/E30 (EC naproxen 500 mg and non-EC        esomeprazole 30 mg) BID.    -   Treatment B: 1 tablet PN 400/E20 (EC naproxen 500 mg and non-EC        esomeprazole 20 mg) BID.    -   Treatment C: 1 tablet PN 400/E10 (EC naproxen 500 mg and non-EC        esomeprazole 10 mg) BID.    -   Treatment D: EC E20+naproxen (1 tablet non-EC naproxen 500 mg        and 1 capsule EC esomeprazole 20 mg in the AM and 1 tablet        non-EC naproxen 500 mg in the PM)

All treatments were administered by study personnel 60 minutes prior tomeals (i.e. doses were taken 60 minutes prior to breakfast (after anover night fast, for the AM dose) and/or 60 minutes prior to dinner (forthe PM dose) for 9 days). The study medications administered BID wereadministered approximately 10 hours apart. Prior to administration ofthe Day 1 AM dose of study drug, the pH probe was placed to monitorintragastric pH for a period of 24 hours. The distal electrode wasplaced 10 cm below the LES with the proximal electrode placed 5 cm abovethe LES using the LES locator and/or by use of formal esophagealmanometry by the investigator. The position of the distance of theelectrode from the nostrils was recorded to facilitate the 24-hourintragastric pH assessments.

In addition, a pre-AM dose blood sample was collected. Post-AM doseblood samples were drawn approximately: 10, 20, 30 and 45 minutes and 1,1.5, 2, 2.5, 3, 4, 6, 8, 10 (pre-PM dose blood sample), 10.17, 10.33,10.5, 10.75, 11, 11.5, 12, 12.5, 13, 14, 16, 18, 20 and 24 hours for PKassessments. After AM dosing on Day 2, subjects were discharged from thePhase 1 unit and instructed to return for the next dosing in the PM ofDay 2 and on Days 3-8 to receive the AM and PM doses. Subjects wereconfined to the Phase 1 unit in the PM of Day 8 in preparation for the24-hour PK and pH assessments on Day 9. Monitoring of pH and bloodsample collection on Day 9 was as described above for Day 1. The pHprobe was removed in the AM on Day 10. Final PK samples were collectedin the AM of Day 10.

Subjects were instructed to return to the Phase 1 unit for subsequenttreatment periods and reminded of the timing for the next treatmentperiod (i.e., the wash-out period of at least 12 days betweentreatments). In each subsequent treatment period, the same procedureswere performed as during the first period, and final study procedureswere performed on Day 10 of the last treatment period or whenever asubject discontinued from the study.

The PK measurements used in this study are assessments commonly used inPhase I studies.

Measuring Intragatric pH

The procedure used to measuring intragastric pH is standard commonlyused in assessing the pharmacodynamic effect of acid-suppressing drugs.A Medtronics Digitrapper pH data logger (Medtronics, Minneapolis, Minn.)was used to record pH. The 24-hour pH assessments were performed on Days1 and 9. The pH recording system measured the difference in potentialbetween the recording and reference electrodes in the tip of the probeand stored this value every couple of seconds. The pH data was providedto a third party blinded to the assigned treatment groups. The thirdparty evaluated the data to determine the validity of the pH recordingsbased on the following established criteria: At least 20 hours of validpH data within a pre-specified reference range; No technical failures ofthe pH recording; and Less than 1 continuous hour with pH data outsidethe reference range.

Collection of Samples

PK blood samples were collected in 6 mL sodium heparin VACUTAINER tubesand stored on ice until centrifuged within 30 minutes of sample draw forapproximately 10 minutes at 3000 rpm (approximately 1800×g) in arefrigerated centrifuge maintained at approximately 4° C. Plasmasupernatant was withdrawn and frozen at −20° C. or colder within 60minutes of collection. Samples were divided into 2 equal aliquots, with1 tube being used for naproxen analysis and the other for esomeprazoleanalysis. Samples were kept frozen at −20° C. and shipped overnight toPPD Development, Richmond Va. for analysis at the end of the study.

Analysis of Esomeprazole in Plasma Assay Methods

Esomeprazole is optically stable and the degree of conversion from the Sto the R enantiomer in humans is negligible. Thus sample analysis foresomeprazole was performed using the validated high performance liquidchromatography tandem mass spectrometry (HPLC/MS/MS) method foromeprazole. This method was developed and validated by PPD Development,Richmond, Va.

Assay methods were generally performed as essentially describedhereinbelow:

A 100 μL aliquot of human plasma containing the anti-coagulant (sodiumheparin) and the analytes was fortified with the internal standard(deuterated analog of omeprazole). The analytes were isolated by solidphase extraction (SPE) using a Phenomenex Strata-X (10 mg) 96-well SPEplate. The final extract was analyzed by HPLC with MS/MS detection usinga Micromass Quattro Micro, triple quadrupole instrument. Chromatographicretention and separation of the analytes were obtained on BetasilSilica-100 analytical column (3×50 mm, 5 μm particle size) using agradient mobile phase program. Mobile phase A consisted of 0.1% formicacid in acetonitrile and mobile phase B consisted of 0.1% formic acid.The analytes were detected by MS/MS with positive electrosprayionization in the mode of multiple reaction monitoring (MRM), with ionsmonitored for omeprazole (m/z 346→198) and deuterated omeprazole (m/z349→198).

Quantification was by analyte to internal standard peak area ratio. Thelinear range of quantitation was 1 to 1000 ng/mL in human plasma, with alower limit of quantification (LLOQ) of 1 ng/mL. The assay was validatedin terms of specificity, precision, accuracy, and sample stability.

Assay Performance

A set of 8 calibration standards ranging from 1.00 to 1000 ng/mL andquality control (QC) samples at 5 different concentrations (2.60, 8.00,30.0, 130, and 750 ng/mL) of each analyte were prepared and stored at−20° C. Between-batch precision and accuracy for analysis of the QCsamples were determined from batch analyses of clinical samples in thisstudy. Precision was measured as the percent coefficient of variation (%CV) of the set of values obtained for each QC level. Accuracy wasexpressed as the percent difference of the mean value from thetheoretical concentration at each QC level.

The inter-assay CV of the QCs for the omeprazole runs ranged from 3.44%to 5.88%, with mean percent differences from theoretical ranging from0.329% to 1.80%. The differences of back-calculated calibration curvevalues from nominal values ranged from −2.87% to 1.54%. For theanalytical runs, which contained diluted subject samples, theappropriate level quality control pool was diluted and analyzed in asimilar manner to validate the dilution of study samples. The % CV ofthe diluted QCs for the run ranged from 0.599% to 2.74% with meanpercent differences from theoretical ranging from −1.24% to 3.99%.

Analysis of Naproxen in Plasma Assay Methods

Concentrations of naproxen in human plasma were generally determinedessentially as described hereinbelow using a validated HPLC method withfluorescence detection developed and validated at PPD Development,Richmond, Va.

A 100 μL aliquot of human plasma containing sodium heparin and theanalytes was combined with the internal standard solution(2-naphthylacetic acid) and diluted with potassium chloride. The analyteand the internal standard were isolated using liquid-liquid extraction.Chromatographic retention and separation of the analytes was obtained ona Symmetry C18 column (4.6×150 mm, 5 μm particle size) using anisocratic mobile phase consisting of 45% acetonitrile: 55% 14.8 mMphosphate buffer. The analytes were detected by fluorescence usingexcitation and emission wavelengths of 230 nm and 370 nm, respectively.

Quantification was by analyte to internal standard peak height ratio.The nominal range of the method was 0.10 to 100 μg/mL for naproxen inhuman plasma with an LLOQ of 0.10 μg/mL.

Assay Performance

A set of 8 calibration standards ranging from 0.1 to 100 μg/mL and QCsamples at 5 different concentrations (0.28, 0.80, 3.0, 12.0 and 76.0μg/mL) of the analyte were prepared and stored at −20° C. Between-batchprecision and accuracy for analysis of the QC samples were determinedfrom batch analyses of clinical samples in this study. Precision wasmeasured as the % CV of the set of values obtained for each QC level.Accuracy was expressed as the percent difference of the mean value fromthe theoretical concentration at each QC level.

The inter-assay CV of the QCs for the naproxen runs ranged from 2.22% to9.59%, with mean percent differences from theoretical ranging from−3.59% to 0.933%. The differences of back-calculated calibration curvevalues from nominal values ranged from −4.73% to 3.79%. For theanalytical run that contained diluted subject samples, the appropriatelevel of QC samples was diluted and analyzed in a similar manner tovalidate the dilution of study samples. The % CV of the diluted QCs forthe run was 4.12% with a mean percent difference from theoretical of−1.54%.

Statistics and Analysis

Data were summarized by reporting the frequency and percentage ofsubjects in each category for categorical and ordinal measures, andmeans, standard deviation or standard error, medians, and ranges forcontinuous measures. All statistical analyses and data listings werecompleted using the SAS® system, version 8.2 or higher.

Three analysis populations were used for analysis:

1) Intent-to-Treat (ITT) population: all randomized subjects who hadvalid pH data for at least 1 treatment period. A subject was consideredto have valid pH data for each treatment period if the subject receivedall doses of study medication per protocol, had at least 20 hours ofvalid pH data determined by the clinical investigator, did not havetechnical failures of the pH recording, and did not have one continuoushour or more with pH data outside the reference range.

2) Per-Protocol (PP) population: all ITT subjects who had valid pH datafor all four treatment periods and did not violate the protocol in a waythat would have significantly impacted the evaluation of PD endpoints.

3) PK population: all randomized subjects who received all doses ofstudy medication for at least one treatment period and had adequateblood sampling to determine the PK parameters of the study drugs.

Pharmacodynamic Endpoints

For each Digitrapper session, separate plots of the esophageal andintragastric pH readings for each subject were prepared and reviewed fornon-valid pH data. Particular attention was paid to recorded pH valuesthat were outside the range from 0.6 to 8.0. Values considered by theinvestigator to be unlikely to have occurred due to a reasonableexpectation of method variability, and which persisted to such an extentas to suggest possible transient unreliability of the equipment, wereidentified and excised from the database. Other apparent ‘flat-lining’of the pH readings could also result in a determination of non-validdata.

The PD endpoints were summarized by treatment and analyzed by Analysisof Variance (ANOVA). The ANOVA model included sequence, period, andtreatment as fixed effects, and subject within sequence as a randomeffect. The least square (LS) means for each treatment, the differenceof LS means between each of the PN 400 treatments and the activecontrol, and 95% confidence intervals (CIs) for all treatmentdifferences were calculated. Both ITT and PP populations were used forthe PD analysis. The PP population was the primary analysis population.In addition, the percent time of pH>3.0 and >5.0 on Days 1 and 9 wasanalyzed in a similar fashion as the percent time of pH>4.0. Mean pHdata over 24 hours on Days 1 and 9 were plotted by treatment.

From a previous study, the within-subject standard deviation (SD) ofpercent time of pH>4.0 was 10%. The current study planned to enroll 28subjects with the aim to have 24 evaluable subjects for analysis. Atotal of 24 subjects provides 80% power to reject the null hypothesisthat the difference between each of the PN 400 treatments and the activecontrol in percent time of pH >4.0 over 24 hours is <-8% using apairwise t-test with a one-sided significance level of 0.05.

Primary Pharmacodynamic Endpoint: Percent Time Intragastric pH>4.0 onDay 9

Results from Day 9 are set forth in Table 4. On Day 9, both PN 400/E30and PN 400/E20 treatments resulted in a greater percent time withintragastric pH>4.0 than treatment with EC E20+naproxen. PN 400/E10 hadthe lowest percent time with intragastric pH>4.0 and was also the mostvariable treatment as evidenced by the high % CV in Table 4.

TABLE 4 Percent Time of pH Greater than 4.0 - Day 9 - Per-ProtocolPopulation D A B C EC E20 + PN 400/E30 PN 400/E20 PN 400/E10 naproxen N= 25 N = 25 N = 25 N = 25 % Time of pH > 4.0 Mean (SD) 76.50 (12.26)71.35 (13.01) 40.85 (22.51) 56.85 (10.06) Median 78.79 70.42 35.76 55.14% Coefficient of variation 16 18 55 18 Range 49.79-95.32 51.76-97.6110.30-85.26 40.63-75.51 LS Mean (SD) 76.75 (3.02)  71.46 (3.02)  41.09(3.02)  57.23 (3.02)  A vs. D B vs. D C vs. D LS Mean Difference (SE)19.52 (3.25)  14.23 (3.25)  −16.14 (3.25)    — 95% Confidence Interval13.04-26.01  7.75-20.71 −22.26-−9.66  —

On Day 1, the LS mean percent time intragastric pH>4.0 ranged from 13%with PN 400/E10 to 28% with PN 400/E30. Treatment differences comparedto EC E20+naproxen were small. Only PN 400/E30 (28%) had a statisticallysignificant, greater percent time with pH>4.0 compared to ECE20+naproxen (21%).

As shown in FIG. 1, there were three increases in pH throughout the daywhich were associated with food intake at 1, 6 and 11 hours, forbreakfast, lunch and dinner, respectively. These increases in pHoccurred approximately one hour after each meal for all treatments.Following the AM dose of PN 400 on Day 9, the pH increase occurredapproximately one hour earlier than the food induced increase in pH (seealso FIG. 2).

After the AM dose of EC E20+naproxen, the pH increase occurred at least30 minutes later than PN 400.

The overall pH profiles on Day 9 showed an esomeprazole dose-relatedeffect on intragastric pH beyond the influence of food intake. Theeffect on intragastric pH profiles was similar between PN 400/E30 and PN400/E20, with each of these treatments reflecting a slower return ofgastric contents to lower pH levels after food intake than either thePN400/E10 or EC E20+naproxen treatments.

Results on Day 9 for the ITT population were similar to those from thePP population. The initial Day 9 pH measurements from all treatmentsshowed the mean intragastric pH after an overnight fast was between 2.0and 3.0, which was higher than the initial pH (between 1.0 and 2.0) onDay 1 (FIG. 2).

As shown in Table 4, the primary PD response of this study, i.e.,percent time intragastric pH>4.0 on Day 9, increased with esomeprazoledose in the PN 400 treatments. However, a greater increase in theprimary PD response was observed when esomeprazole dose increased from10 to 20 mg in PN 400, i.e., from 40.9 to 76.5%. There was only a smallincrease in intragastric pH>4.0, from 71.4 to 76.5%, as the esomeprazoledose increased from 20 to 30 mg in PN 400.

Secondary Pharmacodynamic Endpoint: Percent Time Intragastric pH>4.0 onDay 1

Results from Day 1 are set forth in Table 5. The LS mean percent timeintragastric pH>4.0 ranged from approximately 13% with PN 400/E10 toapproximately 28% with PN 400/E30.

TABLE 5 Percent of Time with Intragastric pH Greater than 4.0 - Day 1 -Per-Protocol Population Treatment D A B C EC E20 + PN 400/E30 PN 400/E20PN 400/E10 Naproxen N = 25 N = 25 N = 24 N = 25 % Time pH > 4.0 Mean(SD) 27.79 (22.63) 20.50 (16.61) 12.81 (11.11) 21.34 (13.63) Median19.96 15.26 9.09 16.82 % CV 81 81 87 64 Range  1.77-89.61  4.35-74.40 3.00-53.75  3.16-58.20 LS Mean (SE) 27.90 (3.31)  20.58 (3.31)  12.66(3.35)  21.51 (3.31)  A vs. D B vs. D C vs. D LS Mean Difference (SE)6.39 (3.18) −0.92 (3.18)   −8.85 (3.22)   — 95% Confidence Interval 0.04-12.75 −7.28-5.43   −15.28-−2.42  —

Mean pH data over 24 hours on Day 1 is presented in FIG. 2. The pHprofiles on Day 1 showed that following an overnight fast, the meanbaseline intragastric pH was low, between 1.0 and 2.0, prior to anytreatment. There were three pH increases above pH 4.0 throughout the daythat were associated with food intake at 1, 6 and 11 hours. The increasein intragastric pH occurred at approximately one hour after each mealfor all treatments. There was only a minimal effect of any of the studytreatments on intragastric pH, beyond the effect of food, throughout thefirst 24 hours on the first day of treatment.

Other Pharmacodynamic Findings

Analysis of percent time of pH>3.0 and >5.0 on Day 9 resulted in asimilar pattern statistically as that of the primary endpoint of percenttime pH>4 on Day 9 for PP population, with PN 400/E30 and PN 400/E20showing a greater acid-reducing capacity than EC E20+naproxen, which hada greater capacity than PN 400/E10, based on LS mean differences and 95%CIs. Analysis results of percent time of pH>3.0 and >5.0 on Day 1 weresimilar as results for the primary endpoint of % time pH>4 on Day 1based on the PP population. ITT population results were similar to thoseof the PP population.

As PN 400 is dosed BID, the individual time intervals corresponding tothis dosing regimen, i.e., 0-10 hours and 10-24 hours, were analyzed forpercent time intragastric pH>4.0 on Day 9. The results indicated thatfor the 0-10 hours period, PN 400/E30 treatment resulted in a greaterpercent time with intragastric pH>4.0 (84%) than treatment with ECE20+naproxen (71%). While PN 400/E20 also had a high percent timeintragastric pH>4.0 (79%), the results were not statisticallysignificantly different from the EC E20+naproxen treatment. With BIDdosing, both PN400/E30 and PN400/E20 had greater percent timeintragastric pH>4.0 (71% and 66%, respectively) compared to treatmentwith EC E20+naproxen (47%) for the 10-24 hour treatment interval. ThePN400/E10 treatment had a lower percent time intragastric pH>4.0compared to treatment with EC E20+naproxen for both the 0-10 hours (52%)and the 10-24 hours (33%) treatment interval.

Pharmacokinetic Endpoints

On Day 1, PK data analysis was performed for esomeprazole and naproxenplasma profiles obtained from 28 subjects completing PN 400/E30, PN400/E20 and EC E20+naproxen; and 27 subjects completing PN 400/E10.

On Day 9, PK data analysis was performed for esomeprazole or naproxenplasma profiles from 28 subjects completing PN 400/E30 and ECE20+naproxen, and 27 subjects completing PN 400/E20 and PN 400/E10.

PK parameters for esomeprazole were determined following the threedifferent PN 400 treatments and PK parameters for naproxen weredetermined following each of the 4 treatments including peak plasmaconcentration (C_(max)) on Days 1 and 9; time to peak plasmaconcentration (t_(max)) on Days 1 and 9; area under the plasmaconcentration vs time curve from time zero to the last time point withmeasurable drug concentration (AUC_(0-t)) on Days 1 and 9; and theterminal half-life (t½), if possible, following both the AM and PM doseson Days 1 and 9. In addition, the AUC from time zero (time of dosing) to10 hours post-AM dose (AUC_(0-10,am)) and AUC from time zero (time ofdosing) to 14 hours post-PM dose (AUC_(0-14,pm)) and a total daily AUC(AUC₀₋₂₄) were determined on Days 1 and 9. PK parameters foresomeprazole following EC E20+naproxen included C_(max), t_(max),AUC_(t-0), t½, and AUC₀₋₂₄ following the AM dose on both Days 1 and 9.

Statistical analysis was performed using Analysis of Variance (ANOVA) todetermine the point estimate and 90% CI of the Day 9 to Day 1 ratios forthe following parameters for both naproxen and esomeprazole C_(max,am),C_(max, pm), AUC_(0-10, am), AUC_(0-14, pm), and AUC₀₋₂₄.

Plasma esomeprazole and naproxen concentration vs. time data are listedby treatment, study day and subject. The concentration data weresummarized by treatment and study day at each nominal (or scheduled)sampling time using descriptive statistics including mean, SD, % CV,median, minimum and maximum. Plasma concentrations below the LLOQ (i.e.,1 ng/mL for esomeprazole, and 0.10 μg/mL for naproxen) were treated as azero value for calculating descriptive statistics. The mean/median valueat a time point with one or more below the LLOQ (BQL) values wasreported unless the mean/median value was below the LLOQ of the assay,in which case the value was reported as BQL. Individual subject plasmaconcentration vs time curves were plotted against the actual samplingtime, and the mean/median plasma concentration vs. time curves wereplotted against nominal sampling time by treatment.

The plasma concentration vs. time data of each analyte were subjected tonon-compartmental analysis using WinNonlin version 4.1 (PharsightCorporation, Mountain View, Calif.). The actual blood sampling time foreach sample was used for PK data analysis. For analyte concentrationsresulting from BID doses, i.e., esomeprazole in Treatments A, B, and Cor naproxen in all 4 treatments, PK analysis was performed separatelyfor the plasma profiles obtained after the AM and PM doses. Thus, theactual post-dose sampling times for concentration vs. time profilesafter the PM dose were calculated based on the elapsed time from theactual dosing time of the PM dose.

For PK analysis, plasma concentrations below the LLOQ (BQL value) inindividual profiles of each analyte were handled as follows. If thevalue occurred in a profile during the absorptive phase of the profile,i.e., before the maximum concentration in a profile was observed, it wasassigned a value of zero concentration. A single BQL value occurringbetween two measurable analyte concentrations, not in the absorptivephase of a profile, was generally omitted. If two or more BQL valuesoccurred in succession, post peak time (or during the eliminationphase), the profile was determined to have terminated at the last timepoint with measurable analyte concentration of the profile.

PK parameters calculated for esomeprazole (following each of the threePN 400 treatments) and for naproxen (following each of the 4 treatments)on Days 1 and 9 included the following: Maximum observed plasmaconcentration following the AM dose (C_(max,am)) and following the PMdose (C_(max,pm)); Time to peak plasma concentration following the AMdose (t_(max,am)) and following the PM dose (t_(max,pm)); Time to thefirst measurable plasma concentration following the AM dose (tlag,am)and following the PM dose (t_(lag, pm)); Area under the plasmaconcentration vs. time curve (AUC) from time zero to the last time pointwith measurable drug concentration (tlast) following the AM dose(AUC_(0-t,am)) and following the PM dose (AUC_(0-t,pm)), calculatedusing the linear-up and log-down trapezoidal method in WinNonlin;Apparent first-order elimination rate constant (λ_(z,am) and λ_(z,pm)),determined, if data permit, by the slope of the apparent terminallog-linear phase of the plasma drug concentration vs. time curve usingat least 3 time points; Apparent plasma half-life (t½), if data permit,determined as 0.693/λ_(z) following the AM and PM doses, i.e., t½,_(am)and t½,_(pm), respectively; AUC from time zero (time of AM dosing) to 10hours after the AM dose (AUC_(0-10,am)), if necessary, withextrapolation using λ_(z,am) estimate from t_(last) to 10 hrs post theAM dose; AUC from time zero (time of PM dosing) to 14 hours after the PMdose (AUC_(0-14,pm)), if necessary, with extrapolation using λ_(z,pm)estimate from λ_(last) to 14 hrs post PM dose; and Total daily AUC(AUC₀₋₂₄) from time zero (time of AM dosing) to 24 hours after the AMdose, which is determined as AUC_(0-10,am)+AUC_(0-14,pm).

The PK parameters calculated for esomeprazole following Treatment Dafter the AM dose on Days 1 and 9 included C_(max), t_(max), AUC_(0-t),t½ and AUC₀₋₂₄. The same methods as described above were applied.

Descriptive statistics, including mean, SD, % CV, median, minimum andmaximum, were calculated for all PK parameters of naproxen andesomeprazole by treatment and study day. Geometric mean and associated95% confidence interval (CI) were also calculated for all PK parameters,except t_(max).

Statistical analysis was performed using ANOVA to determine the pointestimate and associated 90% CI of the Day 9 to Day 1 ratios for thefollowing parameters: C_(max,am,) C_(max,pm), AUC_(0-10,am),AUC_(0-14,pm), and AUC₀₋₂₄ for esomeprazole data in each of the three PN400 treatments, and for naproxen data in each of the 4 treatments. Foresomeprazole data from Treatment D, the Day 9 to Day 1 ratios forC_(max) and AUC₀₋₂₄were determined Natural log-transformed C_(max) andAUC values were used for the analyses, thus geometric least-squares meanratios for each parameter were determined

Dose proportionality in the C_(max,am), C_(max,pm), AUC_(0-10,am),AUC_(0-14,pm), and AUC₀₋₂₄ of esomeprazole from the three PN400treatments was analyzed on Days 1 and 9 separately, using the powermodel as follows:

y=a*(dose)^(b)

ln(y)=ln(a)+b*ln(dose)

where y is the PK parameter value and ln=natural log. The power modelincluded ln(dose) and period as fixed effects and subject as a randomeffect.

Esomeprazole

Table 6 summarizes the results from the PK analysis that was performedfor esomeprazole plasma concentration vs. time data for the 28 subjectswho completed PN 400/E30 and EC E20+naproxen treatments and 27 subjectswho completed PN 400/E10 treatment on Days 1 and 9; and 28, and 27subjects who completed PN 400/E20 treatment on Day 1 and Day 9,respectively.

TABLE 6 Summary of Esomeprazole Pharmacokinetic Results AUC_(0-10, am)or Day/Dose C_(max) t_(max) AUC_(0-14, pm) AUC₀₋₂₄ t½ Treatment Time(ng/mL) (hr) (hr * ng/mL) (hr * ng/mL) (hr) A 1 487 0.50 591    0.892 PN400/E30 AM  (82) (0.33-1.50) (108) (35) 1 187 1.50 388 978    1.11 PM(132) (0.33-4.00) (137) (115) (62) 9 1584 0.50 2779     1.26 AM  (39)(0.17-1.50) (45) (25) 9 810 1.00 2066  4911     1.46 PM  (59)(0.33-8.00) (53) (42) (34) B 1 292 0.50 350    0.846 PN 400/E20 AM  (77)(0.20-1.50) (113) (42) 1 96.6 1.49 206 556    0.994 PM (104) (0.33-3.00)(141) (119) (55) 9 715 0.50 1216     1.12 AM  (52) (0.17-1.50)  (69)(33) 9 428 0.75 919 2134     1.31 PM  (73) (0.33-3.00)  (84)  (74) (42)C 1 138 0.33 148    0.810 PN 400/E10 AM (71) (0.17-3.10) (111) (48) 1  35.3 1.50   85.7 237    0.878 PM  (84) (0.33-3.00) (179) (133) (50) 9278 0.33 368    0.860 AM  (57) (0.17-1.00)  (89) (41) 9   97.6 1.00 223602    1.09 PM (136) (0.33-2.00) (134) (103) (47) D 1 282 1.50 520 580   1.09 EC E20 + AM  (66) (1.00-16.0)  (64)  (67) (44) naproxen 9 4351.50 1046  1212     1.27 AM  (48) (1.00-14.0)  (54)  (47) (36) Valuesare mean (% CV) for all parameters, except for tmax, which are median(range).

Following oral administration of PN 400 on Day 1, esomeprazoleconcentrations were measurable at 10 minutes after the AM dose, and at20-30 minutes after the PM dose. Plasma esomeprazole concentrationsafter the PM dose were lower than those after the AM dose on both days.C_(max) and AUCs of esomeprazole increased nearly dose proportionallyafter the AM dose on Day 1, but more than dose proportionally after thePM dose on Day 1 and both the AM and PM doses on Day 9. Esomeprazoleconcentrations were much higher on Day 9 than on Day 1 for each PN 400treatment. The geometric least-squares mean AUC₀₋₂₄ ratios, Day 9 to Day1, were 7.13, 4.10, and 2.26 for treatment with PN 400/E30, PN 400/E20,and PN 400/E10, respectively.

Following EC E20+naproxen treatment, the first measurable esomeprazoleconcentration was at 0.5 to 1.5 hrs post dose. To evaluate the effect ofesomeprazole in the PN400/E20 treatment group with the EC E20 in the ECE20+naproxen treatment group, the PK parameters from PN400/E20 and ECE20+naproxen treatment groups were compared. On Day 1, esomeprazoleC_(max,am) mean values were approximately equal for the PN400/E20 and ECE20+naproxen treatments (292 and 282 ng/mL, respectively). The AUC₀₋₁₀mean values on Day 1 from the PN400/E20 treatment were approximatelytwo-thirds that of the EC E20+naproxen treatment (350 vs. 520 hr·ng/mL,respectively). By Day 9, however, the esomeprazole AUC₀₋₁₀ for thePN400/E20 treatment group was greater than the EC E20+naproxen treatmentgroup (1216 vs 1046 hr·ng/mL, respectively) and C_(max,am) from thePN400/E20 treatment group was almost double that of the EC E20+naproxentreatment group (715 vs 435 ng/mL, respectively).

Mean and median plasma esomeprazole concentration vs time profilesfollowing all four treatments were plotted and the mean plots arepresented in FIGS. 3 and 4. These figures demonstrate that esomeprazoleconcentrations following AM or PM doses on Day 1 or Day 9 increased withthe esomeprazole dose in the PN 400 treatments. Furthermore, on bothDays 1 and 9, esomeprazole concentrations after the AM dose were higherthan those after the PM dose for each PN 400 treatment. Following ECE20+naproxen treatment, the mean profiles demonstrate a delayedabsorption peak on both Days 1 and 9 as compared to PN 400. In addition,peak esomeprazole concentrations following EC E20+naproxen treatmentwere lower than those following PN 400/E20, especially on Day 9 (about50% lower).

The pharmacokinetic parameters of esomeprazole following the AM and PMdoses on Day 1 and Day 9 of each treatment group are summarized inTables 7 to 10 below.

TABLE 7 Summary of Esomeprazole Pharmacokinetic Parameters by Study Dayand Dose Time for Treatment A (PN 400/E30) AUC_(0-10, am) or DoseC_(max) t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time Statistics(ng/mL) (hr) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL) (hr) 1 AM Mean 487588 591 0.892 n = 28 % CV 82 109 108 35 Median 325 0.50 352 354 0.810Min 52.1 0.33 59.4 61.0 0.520 Max 1400 1.50 3087 3087 1.96 1 PM Mean 187385 388 978 1.11 n = 28 % CV 132 138 137 115 62 Median 114 1.50 204 207579 0.861 Min 21.1 0.33 37.4 40.3 101 0.593 Max 1290 4.00 2315 2315 54023.89 9 AM Mean 1584 2778 2779 1.26 n = 28 % CV 39 46 45 25 Median 15600.50 2586 2586 1.18 Min 384 0.17 874 879 0.83 Max 3520 1.50 5841 58411.80 9 PM Mean 810 1990 2066 4911 1.46^(a) n = 28 % CV 59 57 53 42 34Median 749 1.00 2090 2159 5488 1.38 Min 13.7 0.33 21.7 342 1519 0.75 Max1970 8.00 4956 4956 9770 2.91 ^(a)n = 27

TABLE 8 Summary of Esomeprazole Pharmacokinetic Parameters by Study Dayand Dose Time for Treatment B (PN 400/E20) AUC_(0-10, am) or DoseC_(max) t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time StatisTics(ng/mL) (hr) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL) (hr) 1 AM Mean 292348 350 0.846 n = 28 % CV 77 114 113 42 Median 209 0.50 245 248 0.696Min 47.1 0.20 57.0 58.1 0.434 Max 916 1.50 1971 1971 1.90 1 PM Mean 96.6203 206 556 0.994 n = 28 % CV 104 144 141 119 55 Median 71.7 1.49 106108 362 0.844 Min 16.0 0.33 24.3 28.6 86.7 0.410 Max 439 3.00 1459 14593429 2.82 9 AM Mean 715 1215 1216 1.12 n = 27 % CV 52 70 69 33 Median700 0.50 947 948 1.03 Min 112 0.17 186 188 0.485 Max 1300 1.50 2931 29311.82 9 PM Mean 428 914 919 2134 1.31 n = 27 % CV 73 85 84 74 42 Median373 0.75 603 642 1727 1.32 Min 30.5 0.33 59.3 63.5 288 0.686 Max 13003.00 2931 2931 5737 3.10

TABLE 9 Summary of Esomeprazole Pharmacokinetic Parameters by Study Dayand Dose Time for Treatment C (PN 400/E10) AUC_(0-10, am) or DoseC_(max) t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time StatisTics(ng/mL) (hr) (hr * ng/mL) (hr * ng/mL) (hr * ng/mL) (hr) 1 AM Mean 138143 148 0.810 n = 27 % CV 71 115 111 48 Median 123 0.33 84.8 105 0.703Min 24.4 0.17 35.0   36.1 0.454 Max 370 3.10 882 882 2.21 1 PM Mean 35.380.6    85.7^(b)  237^(b) 0.878^(a) n = 27 % CV 84 188 179 133 50 Median32.1 1.50 41.8   48.7 155 0.734 Min 4.2 0.33 8.40    9.80   45.9 0.593Max 141 3.00 818 818 1700  2.67 9 AM Mean 278 366 368 0.860 n = 27 % CV57  90  89 41 Median 242 0.33 223 224 0.653 Min 33.0 0.17 41.0   42.60.526 Max 594 1.00 1284 1284  1.85 9 PM Mean 97.6 215  223^(b)  602^(b)1.09^(b) n = 27 % CV 136 137 134 103 47 Median 42.2 1.00 69.9   76.9 3060.944 Min 11.0 0.33 17.3   18.8   63.7 0.370 Max 554 2.00 1076 1080 2186  2.79 ^(a)n = 25; ^(b)n = 26

TABLE 10 Summary of Esomeprazole Pharmacokinetic Parameters by Study Dayand Dose Time for Treatment D (EC E20 + Naproxen) Dose C_(max) t_(max)AUC_(0-t) AUC_(0-10, am) AUC₀₋₂₄ t½ Day Time StatisTics (ng/mL) (hr)(hr * ng/mL) (hr-ng/mL) (hr * ng/mL) (hr) 1 AM Mean 282 567  540^(b) 580^(b) 1.09^(b) n = 28 % CV 66 68  60  67 44 Median 231 1.50 466 471471 0.931 Min 1.1 1.00 143 143 144 0.633 Max 678 16.0 1777 1359  1777 2.56 9 AM Mean 435 1136 1046  1212^(b ) 1.27^(a) n = 28 % CV 48 52  54 47 36 Median 453 1.50 1056 859 1123  1.16 Min 98.0 1.00 292 289 4290.755 Max 939 14.0 2279 2217  2279  2.46 ^(a)n = 25; ^(b)n = 26

Naproxen

Table 11 summarizes the results from the PK analysis that was performedfor naproxen plasma concentration vs. time data for the 28 subjects whocompleted PN 400/E30 and EC E20+naproxen treatments and 27 subjects whocompleted the PN 400/E10 treatment on Days 1 and 9; and 28, and 27subjects who completed PN 400/E20 treatment on Day 1 and Day 9,respectively.

TABLE 11 Naproxen Pharmacokinetic Parameters Day/ AUC_(0-10, am) or DoseC_(max) t_(max) AUC_(0-14, pm) AUC₀₋₂₄ t½ Treatment Time (μg/mL) (hr)(hr * μg/mL) (hr * μg/mL) (hr) A 1   48.1 4.00 259     8.52 PN400/E30 AM(53) (2.00-10.0) (56) (25) 1   68.9 14.0  471 730    12.1 PM (28)(0.50-14.0) (30) (32) (30) 9   80.9 3.00 603     9.17 AM (23)(0.00-8.00) (21) (21) 9   76.2 10.4  648 1251    12.3 PM (23)(0.00-14.0) (20) (16) (27) B 1   44.4 4.00 231     8.75 PN 400/E20 AM(68) (2.00-10.0) (70) (33) 1   71.5 14.0  450  680    11.8 PM (26)(0.00-14.0) (33) (36) (28) 9   86.2 3.00 607     9.42 AM (22)(0.00-8.05) (19) (23) 9   76.8 10.0  678 1275    11.3 PM (18)(0.00-14.0) (16) (15) (28) C 1   57.0 4.00 310    9.24 PN 400/E10 AM(31) (2.00-10.0) (35) (42) 1   68.6 10.0  508 819    12.7 PM (26)(0.00-14.0) (29) (21) (23) 9   87.1 2.50 637    9.91 AM (21) (0.00-8.00)(17) (26) 9   78.6 14.0  672  1309    10.5 PM (17) (1.50-14.0) (19) (15)(23) D 1   65.5 1.50 409     8.85 EC E20 + AM (25) (0.75-6.00) (16) (22)naproxen 1   81.5 1.50 685 1094    15.4 PM (14) (0.50-2.50) (10) (12)(31) 9   90.0 1.50 617     9.32 AM (19) (0.50-4.00) (12) (23) 9   86.51.50 769  1387    14.4 PM (13) (0.75-4.00) (10) (10) (17) Values aremean (% CV) for all parameters, except for t_(max), which are median(range).

Following oral administration of PN 400 on Day 1, the first measurablenaproxen concentrations occurred at about 2 hrs post AM dose. Plasmaexposure to naproxen was comparable among the three PN 400 treatments.Following repeated doses of PN 400, the Day 9 to Day 1 naproxenconcentration ratio was consistent with the expected accumulation basedon the half-life estimates of naproxen. The variability in naproxen AUCbetween AM and PM doses was less on Day 9 than on Day 1, reflecting thatnaproxen levels are approximately at steady state with repeat dosing.C_(max) values were somewhat more variable between the AM and PM doseson Day 1 compared to Day 9, with mean AM levels being lower than mean PMlevels for all treatments on Day 1 and mean AM levels slightly higherthan mean PM levels for all treatments on Day 9.

Following the first (AM) dose of Treatment D on Day 1, plasma naproxenconcentrations were measurable in all subjects at the first samplingtime, i.e., 10 minutes post-dose and then up to 24 hours post AM dose(or 14 hours post PM dose), demonstrating typical performance ofnon-enteric coated naproxen.

Mean and median plasma naproxen concentration vs time profiles followingall 4 treatments are presented in FIGS. 5 and 6.

The PK parameters of naproxen following administration of the AM and PMdoses on Day 1 and Day 9 of each treatment are summarized in Tables 12to 15 below.

TABLE 12 Summary of Naproxen Pharmacokinetic Parameters by Study Day andDose Time for Treatment A (PN 400/E30) AUC_(0-10, am) or Dose C_(max)t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time StatisTics (μg/mL)(hr) (hr * μg/mL) (hr * μg/mL) (hr * μg/mL) (hr) 1 AM Mean 48.1 259 2598.52^(a) n = 28 % CV 53 56 56 25 Median 53.2 4.00 339 339 7.86 Min 0.02.00 0.0 0.0 6.07 Max 82.5 10.0 428 428 13.8 1 PM Mean 68.9 471 471 73012.1^(b) n = 28 % CV 28 30 30 32 30 Median 68.5 14.0 464 464 780 10.8Min 31.9 0.50 190 190 190 7.16 Max 114 14.0 716 716 1092 19.2 9 AM Mean80.9 603 603 9.17^(c) n = 28 % CV 23 21 21 21 Median 80.0 3.00 568 5689.31 Min 44.5 0.00 345 345 5.32 Max 139 8.00 944 944 13.2 9 PM Mean 76.2648 648 1251 12.3^(d) n = 28 % CV 23 20 20 16 27 Median 69.7 10.4 635635 1269 12.0 Min 53.9 0.00 384 384 729 6.56 Max 127 14.0 932 932 174422.1 ^(a)n = 17; ^(b)n = 21; ^(c)n = 26; ^(d)n = 24.

TABLE 13 Summary of Naproxen Pharmacokinetic Parameters by Study Day andDose Time for Treatment B (PN 400/E20) AUC_(0-10, am) or Dose C_(max)t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time StatisTics (μg/mL)(hr) (hr * μg/mL) (hr * μg/mL) (hr * μg/mL) (hr) 1 AM Mean 44.4 231 2318.75^(a) n = 28 % CV 68 70 70 33 Median 50.1 4.00 291 291 7.72 Min 0.002.00 0.00 0.0 6.07 Max 94.4 10.0 490 490 15.1 1 PM Mean 71.5 450 450 68011.8^(b) n = 28 % CV 26 33 33 36 28 Median 69.4 14.0 443 443 756 10.9Min 45.1 0.00 159 157 157 6.70 Max 110 14.0 831 831 977 18.7 9 AM Mean86.2 607 607 9.42^(b) n = 27 % CV 22 19 19 23 Median 85.1 3.00 577 5778.65 Min 53.5 0.00 378 378 5.48 Max 137 8.05 856 856 13.9 9 PM Mean 76.8668 678 1275 11.3^(c) n = 27 % CV 18 16 16 15 28 Median 73.0 10.0 661661 1306 10.9 Min 51.2 0.00 458 458 939 7.97 Max 116 14.0 847 847 165919.2 ^(a)n = 15, ^(b)n = 22, ^(c)n = 20

TABLE 14 Summary of Naproxen Pharmacokinetic Parameters by Study Day andDose Time for Treatment C (PN 400/E10) AUC_(0-10, am) or Dose C_(max)t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time StatisTics (μg/mL)(hr) (hr * μg/mL) (hr * μg/mL) (hr * μg/mL) (hr) 1 AM Mean 57.0 310 3109.24^(a) n = 27 % CV 31 35 35 42 Median 60.3 4.00 339 339 7.88 Min 6.902.00 50.5 50.5 3.36 Max 88.2 10.0 488 488 21.8 1 PM Mean 68.6 508 508819 12.7^(b) n = 27 % CV 26 29 29 21 23 Median 70.0 10.0 512 512 80512.5 Min 30.0 0.00 271 271 454 6.93 Max 97.2 14.0 791 791 1225 20.2 9 AMMean 87.1 637 637 9.91^(c) n = 27 % CV 21 17 17 26 Median 83.9 2.50 654654 9.29 Min 45.0 0.00 332 332 6.88 Max 120 8.00 787 787 16.1 9 PM Mean78.6 672 672 1309 10.5^(b) n = 27 % CV 17 19 19 15 23 Median 73.5 14.0687 687 1328 9.98 Min 62.4 1.50 349 349 681 7.17 Max 109 14.0 953 9531647 16.1 ^(a)n = 22; ^(b)n = 25; ^(c)n = 23.

TABLE 15 Summary of Naproxen Pharmacokinetic Parameters by Study Day andDose Time for Treatment D (EC E20 + Naproxen) AUC_(0-10, am) or DoseC_(max) t_(max) AUC_(0-t) AUC_(0-14, pm) AUC₀₋₂₄ t½ Day Time Statistics(μg/mL) (hr) (hr * μg/mL) (hr * μg/mL) (hr * μg/mL) (hr) 1 AM Mean 65.5409 409 8.85^(a) n = 28 % CV 25 16 16 22 Median 67.0 1.50 411 411 8.44Min 39.9 0.75 293 293 6.17 Max 113 6.00 562 562 14.1 1 PM Mean 81.5 685685 1094 15.4 n = 28 % CV 14 10 10 12 31 Median 80.8 1.50 662 662 106814.7 Min 58.2 0.50 592 592 909 9.04 Max 107 2.50 855 855 1398 32.8 9 AMMean 90.0 617 617 9.32 n = 28 % CV 19 12 12 23 Median 87.0 1.50 619 6199.39 Min 59.4 0.50 493 493 5.77 Max 126 4.00 793 793 15.4 9 PM Mean 86.5769 769 1387 14.4 n = 28 % CV 13 10 10 10 17 Median 89.6 1.50 760 7601371 14.7 Min 67.3 0.75 619 619 1130 10.5 Max 123 4.00 930 930 1723 21.1^(a)n = 27.

Drug Concentrations or Pharmacokinetics in Relation to PharmacodynamicMeasurements

As shown in FIG. 7, the relationship between the mean total plasmaexposure to esomeprazole, i.e., AUC₀₋₂₄ on Day 9 (representingsteady-state exposure), and the mean percent time with intragastricpH>4.0 on Day 9 (the primary PD endpoint) can be described by a typicalpharmacological maximal response (E_(max)) model defined below:

Effect=(E _(max)*AUC₀₋₂₄)/(EC50+AUC₀₋₂₄), where

-   -   Effect=Mean percent time intragastric pH>4.0 on Day 9 (assuming        zero time intragastric pH>4.0 when esomeprazole AUC₀₋₂₄ equals        zero)    -   E_(max)=Maximal Effect    -   EC50=Plasma mean AUC₀₋₂₄ required to produce 50% of the Maximal        Effect

The E_(max) was estimated to be 90.4% of time with intragastric pH>4.0over the daily interval at steady state. The AUC₀₋₂₄ value required toachieve half (or 50%) of the maximal response was estimated to be 713hr*ng/mL. Following PN 400/E20, the PD response had achieved about 80%of the maximal response, which was only slightly less than that (85% ofE_(max)) achieved by PN 400/E30.

Repeat doses of PN 400/E30 and PN 400/E20 resulted in faster onset ofincreased intragastric pH (at about 1 hour post dose) than ECE20+naproxen, which was at about 1.5 hours post-dose (FIG. 1).

As shown in the FIG. 8A, the release of naproxen from PN 400 occurred1.5 to 2 hours post AM dose. Before naproxen was absorbed to peakconcentrations following PN 400 treatment, intragastric pH had alreadyachieved high levels, well above pH 4.0 (FIG. 8A). In fact, with the BIDregimen of PN 400/E20, given 1 hour before a meal, the intragastric pHwas maintained at above 4.0 for greater than 70% of time over a 24-hourperiod, which would encompass any rise in plasma naproxen concentrationsthroughout the day.

In contrast, EC E20+naproxen produced peak naproxen concentrations thatpreceded the increase in intragastric pH (FIG. 8B). In fact, peaknaproxen concentrations occurred 1 to 2 hours post dose, which coincidedwith the time period when intragastric pH was lowest (FIG. 8B).

Example 2

A randomized, open-label, 4-way crossover study was conducted toevaluate naproxen and esomeprazole plasma levels in healthy subjectsfollowing oral administration of PN 400, enteric-coated naproxen 500 mgplus enteric-coated esomeprazole 20 mg, enteric-coated naproxen 500 mgalone, and enteric-coated esomeprazole 20 mg alone. The study consistedof 4 single-dose treatment periods with a washout period of at least 12days between periods. Subjects received a single dose of each of thefollowing four treatments following a 10-hour overnight fast in acrossover fashion based on a randomization schedule with balancedtreatment sequences.

Treatment Study Drug A PN 400 (delayed-release naproxen 500mg/immediate-release esomeprazole 20 mg) tablet B EC naproxen (ECNAPROSYN ®) 500 mg tablet plus EC esomeprazole (NEXIUM ®) 20 mg capsuleC EC naproxen 500 mg tablet (EC NAPROSYN ®) D EC esomeprazole 20 mgcapsule (NEXIUM ®) EC = enteric-coated

Plasma concentration vs. time profiles of naproxen were obtained fromthe analysis of frequent blood samples taken over a 72-hour post-doseperiod following each treatment. Plasma concentration vs. time profilesof esomeprazole were obtained from the analysis of blood samples takenover a 12-hour post-dose period following Treatment A (PN 400),Treatment B (EC naproxen+EC esomeprazole), and Treatment D (ECesomeprazole alone).

Pharmacokinetic (PK) parameters of naproxen and esomeprazole weredetermined from the plasma concentration vs. time profiles usingnoncompartmental methods. PK parameters included maximum plasmaconcentration (C_(max)), time to maximum concentration (t_(max)), lagtime in absorption (t_(lag)), area under the plasma concentration vs.time curve from time zero to the last time point with measurable drugconcentration (AUC_(0-t)), AUC from time zero with extrapolation toinfinity (AUC_(0-inf)), percentage of the AUC_(0-inf) that isextrapolated from the last time point with measurable drug concentrationto infinity (% AUC_(extrap)), and terminal elimination half-life(t_(1/2)).

The relative bioavailability of esomeprazole from PN 400 was determinedby the ratios of AUC_(0-t), AUC_(0-inf), and C_(max) of esomeprazole forTreatment A vs. Treatment B, and Treatment A vs. Treatment D. Therelative bioavailability of naproxen from PN 400 was determined by theratios of AUC_(0-t), AUC_(0-inf), and C_(max) of naproxen for TreatmentA vs. Treatment B, and Treatment A vs. Treatment C. The ratios wereestimated from the analysis of variance (ANOVA) of log_(e)-transformedparameters with sequence, period, and treatment as fixed effects, andsubject within sequence as a random effect. The geometric least-squaresmean (GLSM) ratios between treatments and the associated 90% confidenceintervals for AUCs and C_(max) for each treatment comparison werecalculated.

A total of forty subjects were enrolled and 37 subjects completed thestudy as planned, receiving all four treatments. Plasmaconcentration-time profiles were available from 38, 39, 39, and 39subjects completing Treatments A, B, C, and D, respectively. Fivesubjects had measurable naproxen concentrations (>0.1 μg/mL) in pre-doseplasma samples during 1 or 3 dose periods. Most of the measurablepre-dose concentrations were less than 5% of the maximum concentrationin each profile, and were included in the PK analysis because they wouldhave little impact on the PK parameter estimates. However, two subjects(Subjects 1003 and 1018) had measurable pre-dose naproxen concentrationsin 1 or all 3 dose periods that were >5% of the maximum concentration ofthe profile. In these two subjects, naproxen concentration at each timepoint in each profile was corrected by subtracting the residualconcentration (calculated based on the decay curve from time zero(pre-dose) concentration) from the measured concentration. Subsequently,PK data analysis was based on the corrected naproxen concentrations inthese two subjects.

In general, plasma naproxen concentrations were not measurable atsampling times before 2 hours post dose in the majority of subjectsreceiving Treatment A, or before 1.5 hours post dose in the majority ofsubjects receiving Treatment B or C. Plasma naproxen concentrations weremeasurable up to 72 hours post dose in all subjects after eachtreatment. All three treatments show very similar mean/median plasmanaproxen profiles, with Treatment A (PN 400) showing slightlyright-shifted (delayed) profiles (see FIG. 9).

Except in one subject in one dose period, none of the pre-dose plasmasamples had quantifiable esomeprazole concentrations (all were <1ng/mL). Following Treatment A (PN 400), plasma esomeprazoleconcentrations appeared rapidly in plasma, generally at the firstsampling time (10 minutes post dose) in 32 out of 38 subjects. Plasmaesomeprazole concentrations were measurable in all subjects at 20minutes post dose of Treatment A. However, following Treatment B or D,plasma esomeprazole concentrations were generally not measurable until0.75 to 1.0 hour post dose. The duration for measurable esomeprazoleconcentrations in plasma was about 8 hours following Treatment A, and upto 10-11 hours post dose following Treatment B or D.

The 8-hour post-dose sample collected during Period 4 for Subject 1036(receiving Treatment B) and Subject 1037 (receiving Treatment D)appeared to have been inadvertently switched. However, this potentialsample switch could not be verified, thus PK data analysis was performedby including and excluding this time point in both subjects. Treatment A(PN 400) showed immediate-release characteristics in esomeprazole plasmaprofile, and Treatments B and D showed delayed-release characteristicsin esomeprazole plasma profile with right-shifted curves (see FIG. 10).

A summary of naproxen and esomeprazol PK parameters by treatment areprovided in Tables 16 and 17 below.

TABLE 16 Summary of Naproxen PK Parameters by Treatment C_(max) t_(max)t_(lag) AUC_(0-t) AUC_(0-inf) t_(1/2) Treatment Statistics (μg/mL) (hr)(hr) (hr * μg/mL) (hr * μg/mL) (hr) A Mean 66.9 6.15 1.98 1226 1326 18.9PN 400 % CV 22 58 53 15 17 14 (N = 38) Median 66.2 5.25 1.50 1232 132419.0 Min 37.8 2.50 0.00 664 683 9.20 Max 97.0 20.2 5.00 1644 1804 26.8 BMean 74.3 4.95 1.22 1263 1374 19.6 EC Naproxen + % CV 22 96 88 15 17 14EC Eso Median 74.0 3.50 1.00 1254 1359 18.8 (N = 39) Min 38.7 0.75 0.00908 985 13.1 Max 114 24.0 4.00 1863 2107 26.1 C Mean 75.3 4.99 1.69 12661375 19.4 EC Naproxen % CV 20 85 69 15 16 11 (N = 39) Median 77.7 4.001.50 1245 1345 19.6 Min 35.2 1.50 0.00 882 894 12.4 Max 96.0 24.0 4.501800 2028 26.2 Eso = esomeprazole

TABLE 17 Summary of Esomeprazole PK Parameters by Treatment C_(max)t_(max) t_(lag) AUC_(0-t) AUC_(0-inf) t_(1/2) Treatment Statistics(ng/mL) (hr) (hr) (hr * ng/mL) (hr * ng/mL) (hr) A Mean 425 0.51 0.03465 467 0.971 PN400 % CV 81 49 234 91 91 45 (N = 38) Median 267 0.450.00 301 302 0.881 Min 58.1 0.33 0.00 104 107 0.600 Max 1330 1.50 0.171940 1949 3.67 B Mean 432 2.50 0.91 801 803 0.945 EC Naproxen + % CV 4854 134 79 79 49 EC Eso Median 369 2.50 0.75 626 628 0.873 (N = 39) Min1.10 1.00 0.00 230 233 0.530 Max 897 9.00 8.00 3840 3871 3.29 D Mean 4552.43 0.87 806 815 0.936 EC % CV 40 34 47 78 81 44 Esomeprazole Median425 2.50 0.75 607 609 0.915 (N = 39) Min 176 0.75 0.33 279 280 0.538 Max915 4.50 2.00 3707 3924 2.86 Eso = esomeprazole

Following oral administration of PN 400, esomeprazole was rapidlyabsorbed without any lag time. As expected, there was delayed absorptionof esomeprazole following administration of EC esomeprazole alone or incombination with EC naproxen. Median t_(max) of esomeprazole followingadministration of EC esomeprazole formulation was about 2 hours longerthan that after administration of PN 400 containing an immediate-releaseformulation of esomeprazole. There was large intersubject variability inesomeprazole C_(max) and AUC values, but not t_(1/2) values for alltreatments.

Statistical analysis results of bioavailability parameters of naproxenand esomeprazole for all treatment comparisons are presented in Tables18 through 20 below.

TABLE 18 Summary of Statistical Analysis of Bioavailability Parametersof Naproxen between Treatments (All Subjects) Treatment Comparison GLSMRatio (90% Confidence Interval) PK Parameter A/C B/C A/B AUC_(0-inf)0.968 1.000 0.968 (hr * μg/mL) (0.937, 1.000) (0.968, 1.032) (0.938,1.000) AUC_(0-t) 0.971 0.999 0.972 (hr * μg/mL) (0.942, 1.001) (0.970,1.029) (0.943, 1.002) C_(max) 0.886 0.984 0.901 (μg/mL) (0.823, 0.954)(0.915, 1.058) (0.837, 0.970) GLSM = geometric least square mean

Similar results were obtained by excluding the two subjects (1003 and1018) with pre-dose naproxen concentrations >5% of C_(max) of theprofile as can be seen in Table 19 below.

TABLE 19 Summary of Statistical Analysis of Bioavailability Parametersof Naproxen between Treatments (excluding Subjects 1003 and 1018))Treatment Comparison GLSM Ratio (90% Confidence Interval) PK ParameterA/C B/C A/B AUC_(0-inf) 0.985 1.003 0.981 (hr * μg/mL) (0.960, 1.011)(0.978, 1.029) (0.956, 1.007) AUC_(0-t) 0.986 1.001 0.985 (hr * μg/mL)(0.963, 1.009) (0.978, 1.024) (0.962, 1.009) C_(max) 0.855 0.966 0.886(μg/mL) (0.803, 0.911) (0.907, 1.028) (0.832, 0.944) GLSM = geometricleast square mean

TABLE 20 Summary of Statistical Analysis of Bioavailability Parametersof Esomeprazole between Treatments Treatment Comparison GLSM Ratio (90%Confidence Interval) PK Parameter A/D B/D A/B AUC_(0-inf) 0.492 0.9790.502 (hr * ng/mL) (0.424, 0.571) (0.843, 1.14) (0.432, 0.585) AUC_(0-t)0.491 0.981 0.500 (hr * ng/mL) (0.422, 0.570) (0.843, 1.14) (0.429,0.583) C_(max) 0.715 0.826 0.866 (ng/mL) (0.536, 0.955) (0.620, 1.10)(0.648, 1.16) GLSM = geometric least square mean

The 90% confidence interval (CI) of the geometric least squares mean(GLSM) ratio of AUC_(0-inf) and C_(max) of naproxen for all treatmentcomparisons fell within the 0.80 to 1.25 limits, indicatingbioequivalence between treatments in terms of naproxen bioavailabilityparameters.

The 90% CI of the GLSM ratio (Test/Reference) of AUC_(0-inf) ofesomeprazole for Treatment B vs. Treatment D fell within the 0.80 to1.25 limits, indicating that esomeprazole AUC values for the twotreatments with EC esomeprazole (with or without concomitant naproxen)are bioequivalent. Based on the point estimates and 90% CI, AUC_(0-inf)of esomeprazole for Treatment A (immediate-release esomeprazole in PN400) were about 50% lower than those of Treatment B or D (i.e., ECesomeprazole) after a single dose administration.

An overview of aderse events (AE) is displayed Table 21 below. Therewere no serious adverse events (SAEs) or withdrawals due to AEs. Theincidence of all AEs ranged from 3% with Treatment C to 15% withTreatment B. The most frequent AEs included dizziness, headache, andnausea or pharyngolaryngeal pain. Most of the AEs were mild in severity.

TABLE 21 Overview of Adverse Events - Safety Population Treatment B A ECNap + C D PN 400 EC Eso EC Nap EC Eso N = 38 N = 39 N = 39 N = 39 n (%)n (%) n (%) n (%) Subjects with at least 1 3 (8) 6 (15) 1 (3) 2 (5)adverse event Subjects with at least 1 0 0 0 0 serious adverse ventDeaths 0 0 0 0 Withdrawals due to adverse 0 0 0 0 events EC =enteric-coated; Nap = naproxen; Eso = esomeprazole A = PN 400 = naproxen500 mg/esomeprazole 20 mg B = EC Nap + EC Eso = enteric-coated naproxen500 mg + enteric-coated esomeprazole 20 mg C = EC Nap = enteric-coatednaproxen 500 mg D = EC Eso = enteric-coated esomeprazole 20 mg

AE data are summarized by system organ class (SOC) and provided in Table22 below. The overall occurrence rate was notably greater with TreatmentB (15%) than with the other treatments (3-8%). The only AEs occurring inmore than 1 subject per treatment period were dizziness, which occurredin 2 subjects (5%) with Treatment B; headache, which occurred in 2subjects with Treatment B; and pharyngolaryngeal pain, which occurred in3 subjects (8%) with Treatment B.

TABLE 22 Treatment-Emergent Adverse Events - Safety Population B A ECNap + C D PN 400 EC Eso EC Nap EC Eso System Organ Class N = 38 N = 39 N= 39 N = 39 Adverse Event n (%) n (%) n (%) n (%) Subjects with at least1 adverse 3 (8)  6 (15) 1 (3) 2 (5) event Nervous system disorders 2 (5)3 (8) 0 2 (5) Dizziness 1 (3) 2 (5) 0 1 (3) Headache 0 2 (5) 0 1 (3)Syncope 1 (3) 0 0 0 General disorders and 1 (3) 1 (3) 1 (3) 0administration site conditions Chest discomfort 0 0 1 (3) 0 Cyst 1 (3) 00 0 Pain 0 1 (3) 0 0 Pyrexia 0 1 (3) 0 0 Respiratory, thoracic and 0 3(8) 0 0 mediastinal disorders Pharyngolaryngeal pain 0 3 (8) 0 0 Cough 01 (3) 0 0 Gastrointestinal disorders 0 1 (3) 0 0 Nausea 0 1 (3) 0 0Injury, poisoning and procedural 1 (3) 0 0 0 complications Head Injury 1(3) 0 0 0 EC = enteric-coated; Nap = naproxen; Eso = esomeprazole A = PN400 = naproxen 500 mg/esomeprazole 20 mg B = EC Nap + EC Eso =enteric-coated naproxen 500 mg + enteric-coated esomeprazole 20 mg C =EC Nap = enteric-coated naproxen 500 mg D = EC Eso = enteric-coatedesomeprazole 20

The only AEs assessed as treatment-related by the investigator werenausea, dizziness and headache in one subject and headache and pyrexiain another subject, each occurring during Treatment B.

1.-18. (canceled)
 19. A method for delivering a pharmaceuticalcomposition to a patient in need thereof, comprising: administering tosaid patient a pharmaceutical composition in unit dose form comprisingnaproxen, or pharmaceutically acceptable salt thereof, and esomeprazole,or pharmaceutically acceptable salt thereof, wherein said esomeprazole,or pharmaceutically acceptable salt thereof, is released from said unitdose form at a pH of from about 0 or greater, wherein one unit dose formis administered as an AM dose and a second dose administered about 10hours later as a PM dose to target: i) a pharmacokinetic (pk) profilefor naproxen where: a) the AM dose has a mean C_(max) of about 81 μg/mLand a median time to maximum concentration (T_(max)) of from about 2.5to about 4 hours, and b) the PM dose has a mean C_(max) of about 76.2μg/mL and a median T_(max) of from about 10 to about 14 hours; and ii) apharmacokinetic (pk) profile for esomeprazole where: a) the AM dose hasa mean area under the plasma concentration-time curve from time zerowhen the AM dose is administered to about 10 hours after the AM dose isadministered (AUC_(0-10,am)) of about 850 hr/*μg/mL, and b) the PM dosehas a mean area under the plasma concentration-time curve from time zerowhen the PM dose is administered to about 14 hours after the PM dose isadministered (AUC_(0-14,pm)) of about 650 hr*μg/mL.
 20. The methodaccording to claim 19, wherein: a) the mean C_(max) for said AM dose ofnaproxen is about 86.2 μg/mL and said median T_(max) is about 3.0 hours;and a) the mean C_(max) for said PM dose is about 76.8 μg/mL and saidmedian T_(max) is about 10 hours.
 21. The method according to claim 19,wherein: a) the mean C_(max) for said AM dose of naproxen is about 80.9μg/mL and said median T_(max) is about 3.0 hours; and b) the meanC_(max) for said PM dose is about 76.2 μg/mL and said median T_(max) isabout 10.4 hours.
 22. The method according to claim 19, wherein a) themean area under the plasma concentration-time curve from time zero whenthe AM dose is administered to about 10 hours after the AM dose isadministered (AUC_(0-10,am)) for said AM dose of esomeprazole is about1216 hr*μg/mL, and b) the mean area under the plasma concentration-timecurve from time zero when the PM dose is administered to about 14 hoursafter the PM dose is administered (AUC_(0-14,pm)) for said PM dose ofesomeprazole is about 919 hr*μg/mL.
 23. The method according to claim19, wherein a) the mean area under the plasma concentration-time curvefrom time zero when the AM dose is administered to about 10 hours afterthe AM dose is administered (AUC_(0-10,am)) for said AM dose ofesomeprazole is about 2779 hr*μg/mL, and b) the mean area under theplasma concentration-time curve from time zero when the PM dose isadministered to about 14 hours after the PM dose is administered(AUC_(0-14,pm)) for said PM dose of esomeprazole is about 2066 hr*μg/mL.24. The method according to claim 19, wherein said pharmaceuticalcomposition further targets a pharmacokinetic (pk) profile having a meanarea under the plasma concentration-time curve from time zero when firstdose is administered to about 24 hours after the first dose isadministered (AUC₀₋₂₄) for esomeprazole is about 1500 hr*μg/mL.
 25. Themethod according to claim 24, wherein the mean area under the plasmaconcentration-time curve from time zero when first dose is administeredto about 24 hours after the first dose is administered (AUC₀₋₂₄) foresomeprazole is about 2000 hr*μg/mL.
 26. The method according to claim24, wherein the mean area under the plasma concentration-time curve fromtime zero when first dose is administered to about 24 hours after thefirst dose is administered (AUC₀₋₂₄) for esomeprazole is about 4911hr*μg/mL.
 27. The method according to claim 19, wherein thepharmaceutical composition further targets a mean % time at whichintragastric pH remains at about 4.0 or greater for about a 24 hourperiod after reaching steady state of at least about 41%.
 28. The methodaccording to claim 27, wherein the mean % time at which intragastric pHremains at about 4.0 or greater for about a 24 hour period afterreaching steady state is at least about 60%.
 29. The method according toclaim 27, wherein the mean % time at which intragastric pH remains atabout 4.0 or greater for about a 24 hour period after reaching steadystate is at least about 71%.
 30. The method according to claim 27,wherein the mean % time at which intragastric pH remains at about 4.0 orgreater for about a 24 hour period after reaching steady state is atleast about 77%.
 31. The method according to claim 19, wherein saidpharmaceutical composition in unit dose form comprises about 500 mg ofsaid naproxen and about 20mg of said esomeprazole.
 32. (canceled) 33.The method according to claim 19, wherein said unit dose form isadministered for a period of at least about 6 days.
 34. The methodaccording to claim 19, wherein said unit dose form is administered for aperiod of at least about 9 days. 35.-37. (canceled)
 38. The methodaccording to claim 19, wherein said patient in need thereof is beingtreated for a disease or disorder selected from pain and inflammation.39. The method according to claim 19, wherein said patient in needthereof is being treated for osteoarthritis, rheumatoid arthritis,ankylosing spondylitis, or a combination thereof.
 40. The methodaccording to claim 19, wherein said unit dose form is a multilayertablet comprising at least one core and at least a first layer and asecond layer, wherein: i) said core comprises naproxen, orpharmaceutically acceptable salt thereof; ii) said first layer is acoating that at least begins to release the naproxen, orpharmaceutically acceptable salt thereof, when the pH of the surroundingmedium is about 3.5 or greater; and iii) said second layer comprisesesomeprazole, wherein said esomeprazole is released at a pH of fromabout 0 or greater.
 41. (canceled)
 42. The method according to claim 40,wherein said esomeprazole is released at a pH of from about 0 to about2. 43.-44. (canceled)
 45. The method according to claim 40, wherein saidmulti-layer tablet is substantially free of sodium bicarbonate. 46.-47.(canceled)